Abstract
YTHDF1 is a well-characterized m6A reader protein that is essential for protein translation, stem cell self-renewal, and embryonic development. YTHDF1 regulates target gene expression by diverse molecular mechanisms, such as promoting protein translation or modulating the stability of mRNA. The cellular levels of YTHDF1 are precisely regulated by a complicated transcriptional, post-transcriptional, and post-translational network. Very solid evidence supports the pivotal role of YTHDF1 in embryonic development and human cancer progression. In this review, we discuss how YTHDF1 influences both the physiological and pathological biology of the central nervous, reproductive and immune systems. Therefore we focus on some relevant aspects of the regulatory role played by YTHDF1 as gene expression, complex cell networking: stem cell self-renewal, embryonic development, and human cancers progression. We propose that YTHDF1 is a promising future cancer biomarker for detection, progression, and prognosis. Targeting YTHDF1 holds therapeutic potential, as the overexpression of YTHDF1 is associated with tumor resistance to chemotherapy and immunotherapy.
Similar content being viewed by others
Background
RNA methylation is an important epigenetic modification in eukaryotic cells and plays a pivotal role in systems development and disease progression [1, 2]. RNA methylation modification is a dynamic biological process, which mainly involves three different components, including the “writers”, “erasers,” and “reader,” [3,4,5]. M6A reader protein recognizes the modification sites on its downstream target genes to produce different biological effects, including RNA splicing, regulation, nucleo-cytoplasmic transport, stability, translation, and degradation [6,7,8,9,10,11].
Among m6A regulators, YTHDF1 is the most abundant m6A reader that functionally connects m6A-modified mRNA to its eventual fate, mostly notably protein translation [12]. Different reading proteins play different biological functions after recognizing m6A modification. For instance, YTHDC1 acts as RNA splicing and nuclear export protein and leads to its unique localization and enrichment in the nucleus [13,14,15]. YTHDC2 plays a crucial role in RNA translation and decay when m6A-modified mRNA is recruited to processing bodies [16,17,18]. YTHDF3 enhances mRNA translation with the help of YTHDF1 and boosts the decay of m6A-modified transcripts mediated by YTHDF2 [19,20,21] and, as a well-characterized m6A reader protein. YTHDF1 is essential for protein translation, embryonic development, and stem cell self-renewal [22,23,24].
YTHDF1 regulates target gene expression by diverse molecular mechanisms, such as promoting protein translation or modulating the stability of mRNA [21, 25,26,27]. The cellular levels of YTHDF1 are precisely regulated by a complicated network at the levels of transcription, post-transcription, and post-translation. Therefore, in this review, we focus on three main aspects of YTHDF1: (a) genetic and biological cell machinery regulation. (b) stem cell self-renewal in central nervous, reproductive, and immune system development, and embryonic development, (d) human cancers progression. We propose that YTHDF1 is a promising future cancer biomarker for detection, progression, and prognosis.
Composition of m6A
M6A modification is a dynamic and reversible biological process, which requires writers, erasers, and readers (Fig. 1). M6A is catalyzed by methyltransferase complex, which includes METTL3 [28], METTL14 [29], WTAP [30], KIAA1429 [31], METTL16 [32], RBM15 [33], and ZC3H13 [34]. The m6A is removed by demethylases such as FTO [35] and ALKBH5 [36]. The m6A erasers promote the transformation of m6A into N6-hydroxymethyladeosine and N6-forms adenosine successively, which is finally hydrolyzed into adenosine. The m6A reader proteins can recognize the m6A-modified RNAs and modulate RNA metabolism, which is divided into different protein families. One class of direct m6A readers proteins contain the YT521-B homology (YTH) domain, including YTH domain family 1–3 (YTHDF1–3) and YTH domain containing 1–2 (YTHDC1–2) in humans [2]. Several heterogeneous nuclear ribonucleoproteins (HNRNPs) fall into the other category, including HNRNPC, HNRNPG, and HNRNPA2B1, which mainly regulate alternative splicing or processing of target transcripts [37]. IGF2 mRNA binding proteins (IGF2BP1/2/3) families [38], and eukaryotic initiation factor (eIF) 3, belong to another subfamily member [39]. Numerous studies have shown that YTHDF1 plays an important role in tumor biology and nontumor lesions by mediating the protein translation of important genes or by affecting the expression of key factors involved in many important cell signaling pathways [14, 40,41,42,43,44,45].
The composition and function of m6A modification. The m6A modification is installed by writers, including METTL3, METTL14, METTL16, CBLL1, WTAP, RBM15B, ZC3H3, VIRMA and KIAA1429. FTO and ALKBH5 are m6A erasers that remove m6A modifications. The m6A-modified RNA reader proteins (YTHDF1/2/3, YTHDC1/2, IGF2BP1/2/3, and HNRNPC/A2B1) are required to recognize m6A and regulate the RNA metabolism
The role of YTHDF1 in the regulation of gene expression
YTHDF1 promotes translation
YTHDF1 promotes its target gene expression via recognition of m6A-edited mRNA and promotion of its translation [46]. However, there are diverse views on the mechanism by which it promotes protein translation. The previous study showed that YTHDF1 promotes translation initiation and subsequent protein translation [47]. For example, Su et al. found that YTHDF1 promotes the formation of the eIF3b translation initiation complex and subsequent YAP translation with depletion of eIF3b or YTHDF1 and the inhibition by METTL3-mediating translation events process [48]. The 5′ UTR region cap structure of eukaryotes helps improve translation efficiency. mRNA translation of JAK2 was mediated by YTHDF1.26 Rapamycin, an inhibitor of cap-dependent protein translation can markedly inhibit the increase of JAK2 protein expression promoted by YTHDF1, which indicates that a cap-dependent mechanism may be involved in YTHDF1-mediated translation [49]. Interestingly, a recent study found that YTHDF1 and YTHDF3 could synergistically promote protein translation efficiency. YTHDF1 and YTHDF3 complexes are paramount to recognizing mRNAs containing m6A modifications, thus promoting the translation of these mRNA. Consistently knockdown of YTHDF1 or YTHDF3 reduces the translation of the m6A-modified transcript [50]. In conclusion, the above results confirmed that YTHDF1 can promote translation by triggering translation initiation and elongation.
YTHDF1 enhances the stability of RNA
Several reports indicated that YTHDF1 plays a critical role in maintaining RNA stability. Wu et al. found that YTHDF1 elevates the stability of c-Myc mRNA catalyzed by METTL3 and promotes c-Myc expression [51]. Another study found that the knockdown of YTHDF1 significantly reduces the half-life of HK2 mRNA, suggesting that YTHDF1 could maintain the RNA stability of HK2 [52]. Additionally, YTHDF1 could combine eEF-2 and IGF2BP3 to promote PDK4 translation elongation and mRNA stability by binding with the m6A-modified 5′ UTR of its mRNA [53].
YTHDF1 is regulated at multi-levels
Considering the critical role of YTHDF1 in gene expression, emerging studies have paid emphasis on the upstream regulatory mechanisms involved in the aberrant expression of YTHDF1 in various diseases (Fig. 2). Previous studies have shown that transcription factors play a crucial role in regulating gene expression. For instance, Li et al., revealed that YTHDF1 plays a critical role in mediating protective autophagy in HCC cells, thereby allowing tumor cells to survive under the hypoxic tumor microenvironment [54]. Utilizing m6A-seq, proteomics, and polysome profiling, the authors showed that YTHDF1 promotes the translation of m6A-modified autophagy-related genes (ATG)-2A and ATG14, thus facilitating the induction of autophagy in HCC cells [55]. Wnt3a induces YTHF1 over-expression and promotes oxaliplatin-induced neuropathic pain in mice [56]. In colorectal cancer, the oncogenic transcription factor c-Myc promotes the expression of YTHDF1 and plays a significant role in colorectal cancer progression [57]. Besides, microRNA-421–3p prevents inflammatory response in cerebral ischemia/reperfusion injury by targeting m6A Reader YTHDF1 to inhibit p65 mRNA translation [58]. Similarly, miR-343 is involved in the regulation of YTHDF1 expression in glioma [59]. In NSCLC, miRNA-376c is down-regulated, while, on the contrary, YTDHF1 is highly expressed. Loading microRNA-376c in extracellular vesicles inhibits properties of non-small cell lung cancer cells by targeting YTHDF1 [54]. LncRNAs play an additional important role in regulating YTHDF1 expression. For example, in lung adenocarcinoma (LUAD) cells, elevated lncRNA LINC00337 expression significantly promotes YTHDF1 expression by sponging the miR-1285-3p thus promoting LUAD cells proliferation and metastasis [60]. In addition, circMAP2K4 positively modulates the YTHDF1 expression by restraining the expression of miR-139-5p and promoting HCC cell proliferation [61]. Taken together, these findings confirmed that YTHDF1 dysregulation can be affected by a series of complex molecular mechanisms. Investigation of the upstream regulatory mechanisms of YTHDF1 dysregulation helps us to better comprehend the biological role of YTHDF1 in cancers and provides possible therapeutic targets for anti-tumor therapy.
The role of YTHDF1 in the physiological process
Numerous studies confirmed that YTHDF1 plays crucial roles in stem cell self-renewal and embryonic development, central nervous and immune systems, we decided to mainly summarize and discuss how YTHDF1 influences both the physiological and pathological progressions in the above three systems (Fig. 3 and Table 1).
The target gene and functions of YTHDF1 in embryonic development, stem cell self-renewal, nervous system development, and immune system development. YTHDF1 recognizes m6A-edited mRNA and facilitates its translation, thus playing a critical role in embryonic development, stem cell self-renewal, nervous system development, and immune system development
YTHDF1 regulates stem cell self-renewal and embryonic development
Stem cells possess replicating ability and multi-directional differentiation potential. Under certain conditions, they can differentiate into a variety of functional cells. According to the development stage of stem cells, they can be divided into embryonic stem cells and adult stem cells. Stem cells are primitive and unspecialized cells, which are not fully differentiated and have the potential of regenerating various tissues and organs. Because of their widespread presence within multicellular tissues, stem cells can progress into a variety of specialized cells through mitosis and differentiation, and generate more stem cells.
Studies indicated that YTHDF1 plays a critical role in regulating stem cell self-renewal. For instance, YTHDF1 was reported to enhance the translation efficiency of JAK2 which, in turn, promotes the pluripotency of embryonic stem cells [49]. A previous study identified that depletion of YTHDF1 significantly impairs cardiomyocyte differentiation and inhibits the expression of cardiomyocyte-specific genes [62]. Another study confirmed that YTHDF1 promotes intestinal cell stemness by recognition and translation of m6A-edited TEAD1 mRNA [63]. Similar results provided evidence that in intestinal stem cells, YTHDF1 is overexpressed via Wnt signaling and that knockdown of YTHDF1 inhibits the stemness of these cells.
Following activation by Wnt, YTHDF1 enhances the translation of TCF7L2/TCF4, thus maintaining their intestinal stem cell population during regeneration [64]. YTHDF1 is highly expressed in human bone marrow mesenchymal stem cells (hBMSCs) whereas depletion of YTHDF1 inhibits osteogenic cell differentiation. Interestingly, YTHDF1 modulates the translation of ZNF839 and ZFP839, resulting in the acceleration of the transcription activity of Runx2-driven osteogenesis of hBMSC [65]. YTHDF1 also promotes proliferation and myogenic differentiation by recognition and increased translation of m6A-edited MyHC, MyoD, and MyoG [66]. It has been shown that YTHDF1 was up-regulated in human and rodent pulmonary hypertension samples, knockdown of YTHDF1 ameliorated PASMC proliferation, phenotypic switching, and pulmonary hypertension development via promoting the translation of MAGED1 both in vivo and in vitro [67]. Taken together, YTHDF1 plays an essential role in embryonic development and stem cell self-renewal.
YTHDF1 regulates the nervous system-related physiological process
The central nervous system (CNS) is the main part of the nervous system, including the spinal cord and brain. Within this system, a large number of nerve cells form a network to transmit, store and process information, generate various psychological activities, and control all animal behaviors. YTHDF1 was up-regulated in the hippocampus of mouse brains and plays a crucial role in spatial learning and memory [68]. YTHDF1 also promotes learning and memory by enhancing the protein translation efficiency of targeted m6A-modified transcripts, under neuronal stimuli [25]. More importantly, a recent study found that YTHDF1 facilitates robo3.1 translation thus driving pre-crossing axon guidance in the spinal cord [46]. Ji et al. found that YTHDF1 is down-regulated in cerebellar granule cells and their axons whereas depletion of YTHDF1 significantly increases the axon growth rates of granule cells in vitro. Consistently knockdown of YTHDF1 in granule cells promotes parallel fiber growth, synapse formation in the cerebellum, and motor coordination ability. Further studies showed that YTHDF1 promotes the translation of Dvl1 and Wnt5a, leading to the activation of the Wnt pathway in cerebellar granule cells [69]. Another study showed that YTHDF1 plays an important role in sciatic nerve lesion-induced global protein synthesis and robust axon regeneration of dorsal root ganglion neurons. Consequently, the extension of regenerating SCG10+ axons was substantially decreased in YTHDF1 knockout mice [70].
YTHDF1 regulates the immune system-related physiological process
The immune system is paramount to maintaining the stability of the environment and physiological balance in the body. It has been shown that depletion of YTHDF1 significantly reduces macrophages, Th1/Th17, and CTL dysfunction together with macrophage-dependent endothelial damage via HMGB1/RAGE [71]. Another study found that infection by bacterium treponema pallidum significantly increases the translation of macrophagic YTHF1 that recognizes and binds to the m6A methylated-SOCS3 mRNA thus decreasing the secretion of inflammatory factors via JAK2/STAT3 pathway inhibition to control the anti-inflammatory response [72]. Knockdown of YTHDF1 promotes the cross-presentation of tumor antigen and the cross-priming of CD8+ T cells via translation of lysosomal cathepsins in Dendritic Cells whereas inhibition of cathepsins significantly increases cross-presentation by wild-type DCs [24].
The role of YTHDF1 in Cancer
Overwhelming evidence substantiates that dysregulation of YTHDF1 is tightly correlated with the malignant progression of various cancer. Therefore, we systematically summarize the recent advances of YTHDF1 in human cancer (Figs. 4, 5, 6 and Table 2).
The target gene and functions of YTHDF1 in esophageal cancer, gastric cancer, colorectal cancer, and liver cancer. YTHDF1 recognizes m6A-edited mRNA and facilitates its translation, thus playing a critical role in the progression of esophageal cancer, gastric cancer, colorectal cancer, and liver cancer
Esophageal cancer
In esophageal cancer (ESC), YTHDF1 is highly expressed and correlated with multiple adverse clinical features [93]. LncRNA-HCP5 directly interacts with YTHDF1 and promotes m6A-modified HK2 mRNA translation, thereby boosting the Warburg effect of ESC cells, and ESC progression [73]. Similarly, YTHDF1 promotes ESC progression via the stabilization of ERBB2 mRNA via recognition of m6A modification [74].
Gastric cancer
Yu et al. demonstrated that in gastric cancer (GC) YTHDF1 is up-regulated and related to aggressive tumor progression and poor overall survival. Knockdown of YTHDF1 inhibits GC cell proliferation and tumor growth whereas YTHDF1 promotes GC progression via translation of FZD7 in an m6A-dependent manner and activation of the Wnt/β-catenin pathway [23]. Zhu et al. found that YTHDF1 accelerates the tumorigenesis and metastasis of GC via recognition of m6A-edited USP14 mRNA and its protein expression [75]. Zhang et al. demonstrated that YTHDF1 promotes oxaliplatin resistance to gastric cancer maintaining the stability of PARP1 in an m6A-dependent manner [76].
Colorectal cancer
YTHDFs is highly expressed in colorectal cancer (CRC) and associated with metastatic disease via increased translation of ARHGEF2 mRNA [94]. On the other hand, another study revealed that YTHDF1 exerts a pro-tumorigenic effect by recognizing and promoting the translation of m6A-modified FZD9 and WNT6 mRNA, leading to the aberrant activation of WNT/β-catenin signaling and ultimately promoting tumorigenicity and stem cell-like activity in CRC [77]. Additionally, YTHDF1 was found to rewire tumor metabolism by promoting the protein translation of glutaminase 1 (GLS1) by targeting the 3′UTR of GLS1 mRNA, which contributes to chemoresistance to cisplatin [78]. YTHDF1 also enhances the transcriptional efficiency of ANKLE1 however it does not maintain ANKLE1 mRNA stability, via recognition of 6A modification thus acting as a tumor suppressor and playing a crucial role in the inhibition of colorectal cancer cell proliferation [79].
Liver cancer
In liver cancer (HCC), YTHDF1 plays a central role in modulating the cell cycle and cell metabolism of the liver cell via tagging Snail, a crucial EMT-related transcription factor, which is essential for the metastasis of HCC cells [80]. Another study demonstrated that YTHDF1 promotes HCC progression via recognition and translation of m6A-modified FZD5 mRNA CDS [81]. Wang et al. reported that YTHDF1 is overexpressed in HCC, induced by hypoxia-related transcription factor HIF-1a, and is correlated with adverse clinical outcomes in HCC patients. YTHDF1 promotes autophagy-related malignancy of HCC via direct binding to m6A-modified ATG2A and ATG14 mRNA, thereby facilitating the translation of ATG2A and ATG14 [55]. Consistently, YTHDF1 knockdown significantly inhibits HCC autophagy, growth, and metastasis [55].
Lung cancer
We have previous results showed that YTHDF1 promotes NSCLC cell proliferation and xenograft tumor formation by mediating the translational efficiency of cyclin D1, cyclin-dependent kinase 2 (CDK2), and CDK4, and that YTHDF1 elimination inhibits de novo lung adenocarcinoma (ADC) progression [22]. Similarly, another study found that YTHDF1 promotes cell growth, invasion, and EMT of NSCLC cells via interaction with eIF3b and increased YAP mRNA translation in m6A dependent manner [82]. Furthermore, YTHDF1 was found to promote lung cancer progression by reading m6A motifs of lncRNA THOR thus enhancing the stability of lncRNA THOR, [83]. Gao et al. demonstrated that LINC00337 is positively regulated by sponging YTHDF1, with the subsequent promotion of LUAD progression [60]. Zhang et al. found that YTHDF1-mediated TGFβR2 mRNA stabilization and increased expression promote the EMT of NSCLC [84]. It has been shown that YTHDF1 is up-regulated in 5-fluorouracil (5-FU) and oxaliplatin-resistant NSCLC cells whereas knockdown of YTHDF1 boosts the cisplatin resistance of NSCLC via modulates the Keap1-Nrf2-AKR1C1 axis [22]. YTHDF1 positive regulates the expression of small nuclear ribonucleic protein PRPF6 via direct recognition ad translation of m6A-edited PRPF6 in LUAD cells [85].
Glioma and glioblastoma
YTHDF1 is elevated in glioblastoma (GBM) and positively regulated by MSI1 whereas both of these proteins are related to worse prognosis in glioblastoma patients [95]. Moreover, high YTHDF1 expression significantly increases in vivo proliferation and tumor growth of glioblastoma [59]. It is noteworthy that YTHDF1 knockdown promotes the sensitivity of glioblastoma cells on TMZ, a major drug for glioblastoma chemotherapy [95].
Prostate and bladder cancer
YTHDF1 is overexpressed in prostate cancer tissues and cells. Patients with higher YTHDF1 expression show a worse prognosis whereas YTHDF1 knockdown significantly inhibits prostate cancer cells proliferation, migration, and invasion via modulating the expression of TRIM44 [96]. Hu et al. found that YTHDF1 is upregulated in prostate cancer and higher expression of YTHDF1 is associated with lymph node metastasis and higher Gleason grades in prostate cancer patients [97]. It has also been reported that YTHDF1 promotes cell growth and progression of bladder cancer via recognition of the m6A sites and translation of ITGA6 [50]. It has been confirmed that CDCP1 was overexpressed in bladder cancer cells, mediated by m6A methyltransferase METTL3, m6A reader YTHDF1 preferentially recognizes m6A residues on CPCP1 3′-UTR and enhances the CDCP1 translation, promotes bladder cancer tumorigenesis in vitro and in vivo [86].
Ovarian Cancer
In addition to ovarian cancer, YTHDF1 is overexpressed in cancer tissues and is correlated with poor prognosis. Mechanistically, YTHDF1 promotes the translation of EIF3C by binding to m6A-modified EIF3C mRNA and concomitantly determines the overall translational output, thereby facilitating tumorigenesis and metastasis of ovarian cancer. EIF3C, as a subunit of the protein translation initiation factor EIF3, also promotes the translation of other proteins in cells [87]. TRIM29 is highly expressed in cisplatin-resistant ovarian cancer cells and correlates with poor prognosis in these patients. Mechanisms research indicated that YTHDF1 promotes the CSC-like characteristics of the cisplatin-resistant ovarian cancer cells via recognition of m6A-edited TRIM29 and increased TRIM29 translation [88].
Breast Cancer
In breast cancer, studies show that hypoxia up-regulates the expression of YTHDF1 that promotes cell proliferation and invasion thus driving tumorigenicity and metastasis. These effects are mediated by the YTHDF1-regulated translation of PKM2 and the subsequent switch to the glycolytic process [89]. Similarly, YTHDF1 is elevated in breast cancer cells and clinical tissue specimens and related to tumor size, lymph node invasion, and distant metastasis in breast cancer patients. YTHDF1 knock-down inhibits breast cancer cell proliferation, and invasion, and induces G0/G1 phase cell cycle arrest. These effects depend on the property of YTHDF1 to recognize and bind to m6A-modified mRNA of FOXM1 leading to enhanced FOXM1 translation efficiency and promotion of breast cancer metastasis [90].
Osteosarcoma
It is well known that YTHDF1 is overexpressed in osteosarcoma (OS) and correlated with the poor prognosis of these patients. Depletion of YTHDF1 suppresses the proliferation, migration, and invasion of the OS cells, via regulation of the expression of CNOT7 [91]. Similarly, YTHDF1 was reported to enhance the translation of methylated YAP transcripts and participate in the tumor progression of OS [92].
Other cancers
Studies have confirmed that m6A RNA modification was dysregulated in PDAC tissues more than in adjacent normal tissues [98]. Huang et al. found that higher YTHDF1 expression correlates with a favorable prognosis and plays a tumor suppressor role in pancreatic ductal adenocarcinoma (PDAC) [99]. YTHDF1 has high copy gains and overexpression in Merkel cell carcinoma, YTHDF1 amplification was positively regulate the expression of MCPyV, and knockdown of YTHDF1 significantly inhibited the Merkel cell proliferation via down-regulate the translation initiation factor eIF3 [80].
Clinical implications of YTHDF1 in human cancers
YTHDF1 as a potential biomarker in human cancer
In summary, most of the studies reported thus far indicate that YTHDF1 can be considered a promising cancer biomarker in a broad range of human tumors: high expression of YTHDF1 is an independent negative prognostic biomarker in patients with NSCLC [22], HCC [55], GC [75], Ovarian [87] and prostate cancer [96], cervical squamous cell carcinoma [100] and CRC [101]. Furthermore, it has been confirmed that elevated YTHDF1 expression is correlated with various malignant tumor behaviors, including invasiveness, and lymph node metastasis. Similarly, YTHDF1 is elevated in prostate cancer and breast cancer tissues, and its high expression is associated with nodal metastasis and lymph node metastasis together with poor prognosis respectively [102]. Similarly, up-regulation of YTHDF1 is positively associated with advanced tumor grade of glioma [59]. In summary, most of the studies reported thus far indicate that YTHDF1 is highly expressed in human cancers and correlates with poor prognosis, implying that YTHDF1 functions as an oncogenic factor.
The impact of YTHDF1 on chemotherapy
Chemoresistance usually results in treatment failure and is correlated with poor prognosis for cancer patients. Emerging work has shown that YTHDF1 plays an important role in cancer chemoresistance. For example, Nishizawa et al. found that YTHDF1, induced by c-Myc, was highly expressed in CRC cells, and knockdown of YTHDF1 could sensitize CRC cells to chemotherapeutic drugs fluorouracil and oxaliplatin [57]. YTHDF1-mediated glutamine metabolism via GLS1 has been shown to promote cisplatin chemoresistance in CRC cells, while the combination of YTHDF1 silencing and cisplatin leads to a synergistic effect in suppressing tumor growth [78]. Consistently, our recent study found that YTHDF1, as a hypoxia adaptation-related gene, is down-regulated in Tibetan domestic mammals compared to lowlanders [22]. Furthermore, the knockdown of YTHDF1 rendered cancer cells resistant to cisplatin treatment via the Keap1-Nrf2-AKR1C1 axis in NSCLC [22]. Therefore, targeting YTHDF1 may combat chemoresistance and alleviate the potential side effects of high-dose cisplatin [22].
The impact of YTHDF1 on immunotherapy
Emerging work has shown that immune checkpoint blockade (ICB) therapy is effective against advanced human cancer, however; only a small subset of cancer patients could benefit from anti-PD-1/PD-L1 immunotherapy [103]. Therefore, there is an urgent need to identify factors that can modulate ICB responses. A previous study identified that YTDHF1 appears to be significantly correlated with DCs in the tumor microenvironment. Genetic ablation of YTHDF1 in mice leads to reduced tumor growth associated with increased tumor infiltration by cytotoxic T cells, whilst simultaneously reducing infiltration of myeloid-derived suppressor cells (MDSC) [24]. Mechanistically, the knockdown of YTHDF1 promotes cross-presentation of tumor-associated antigens by DCs, which activate CD8+ T cell-mediated adaptive immune response. ICB therapeutic response is significantly enhanced in YTHDF1-knockout mice as compared to wild-type mice [24]. Loss of YTHDF1 in tumor cells leads to the recruitment of mature DCs in the tumor, which in turn promotes the infiltration of T helper cells and cytotoxic T cells, as well as the increased production of cytotoxic cytokines. These studies collectively confirmed that the targeting of YTHDF1 in human cancer could reactivate antitumor immunity and potentiate the therapeutic effect of ICB therapy.
Discussions
YTHDF1 is an essential gene required for embryogenesis, organ development, and disease progression. The dynamic expression of YTHDF1 is strictly controlled by a complex regulatory network at multiple levels, including transcription, post-transcription, and post-translation, and its expression balance controls the expression of a downstream target gene that regulates several signaling pathways to participate in cancer progression. Understanding its responsible regulatory mechanism and modulation of its expression in different ways are extremely important prospects for the diagnosis and treatment of human diseases.
In terms of clinical application, YTHDF1 was reported to be an independent marker for the diagnosis and prognosis of human cancer. Accumulating evidence confirmed that YTHDF1 dysregulation correlated with radioresistance and poor clinical outcomes in patients with cancers. Genetic depletion of YTHDF1 sensitizes human tumors to chemotherapy and immunotherapy, suggesting that YTHDF1 antagonists can be potential adjuvants in cancer therapy. In particular, the targeting of YTHDF1 has been shown to mediate a switch from immunological “cold” tumors to “hot” tumors, and thus presents great potential in combination with ICB therapy. Collectively, targeting YTHDF1 represents a promising approach for the future management of human cancers.
YTHDF1 plays a paramount role in embryonic development which certainly imply its relevance also a potential target/biomarker in human physiology. However, there are many problems to be solved. First, m6A modification sites exist in different regions of RNA transcripts, including 3 UTR, CDS, and 5UTR therefore, identifying modifications at different sites may have different effects, regulating the translation of target genes or maintaining their stability. Furthermore, it is unknown which site is more important for its function, and so far there are no YTHDF1 small molecule inhibitors identified yet. Therefore, as described in this review, because of its crucial role in human progression it will be extremely important to develop small molecule inhibitors of YTHDF1 or screen natural compounds that can down-regulation YTHDF1 for cancer treatment.
Conclusions
In summary, YTHDF1 plays a critical role in both human physiological system development and human cancer progression, and it may serve as a promising diagnostic/prognostic biomarker and a potential therapeutic target.
Availability of data and materials
Not applicable.
Abbreviations
- 3’UTRs:
-
3′ Untranslated regions
- CRC:
-
Colorectal cancer
- eIF:
-
Eukaryotic initiation factor
- EMT:
-
Epithelial-mesenchymal transition
- FTO:
-
Fat mass and obesity-associated protein
- IGF2BP:
-
IGF2 mRNA binding protein
- m6A:
-
N6-methyladenosine
- METTL3/14/16:
-
Methyltransferase-like 3/14/16
- RBM15/15B:
-
RNA-binding motif protein 15/15B
- SOCS2:
-
Suppressor of cytokine signaling 2
- SRSF5:
-
SR-like splicing factors 5
- TCF4:
-
Transcriptional factor 4
- USP48:
-
Ubiquitin specific peptidase 48
- VIRMA/KIAA1429:
-
Virlike m6A methyltransferase-associated
- WTAP:
-
WT1-associated protein
- YTHD:
-
YTH domain family of protein
- ZC3H13:
-
Zinc finger CCCH-type containing 13
References
Zhao BS, Roundtree IA, He C. Post-transcriptional gene regulation by mRNA modifications. Nat Rev Mol Cell Biol. 2017;18(1):31–42. https://doi.org/10.1038/nrm.2016.132.
Shi H, Wei J, He C. Where, when, and how: context-dependent functions of RNA methylation writers, readers, and erasers. Mol Cell. 2019;74(4):640–50. https://doi.org/10.1016/j.molcel.2019.04.025.
He PC, He C. M (6) a RNA methylation: from mechanisms to therapeutic potential. EMBO J. 2021;40(3):e105977. https://doi.org/10.15252/embj.2020105977.
Li Z, Brouwer C, He C. Gold-catalyzed organic transformations. Chem Rev. 2008;108(8):3239–65. https://doi.org/10.1021/cr068434l.
Yue Y, Liu J, He C. RNA N6-methyladenosine methylation in post-transcriptional gene expression regulation. Genes Dev. 2015;29(13):1343–55. https://doi.org/10.1101/gad.262766.115.
Frye M, Harada BT, Behm M, et al. RNA modifications modulate gene expression during development. Science. 2018;361(6409):1346–9. https://doi.org/10.1126/science.aau1646.
Hsu PJ, Shi H, He C. Epitranscriptomic influences on development and disease. Genome Biol. 2017;18(1):197. https://doi.org/10.1186/s13059-017-1336-6.
Liu J, Harada BT, He C. Regulation of gene expression by N (6)-methyladenosine in Cancer. Trends Cell Biol. 2019;29(6):487–99. https://doi.org/10.1016/j.tcb.2019.02.008.
Nachtergaele S, He C. Chemical modifications in the life of an mRNA transcript. Annu Rev Genet. 2018;52:349–72. https://doi.org/10.1146/annurev-genet-120417-031522.
Nachtergaele S, He C. The emerging biology of RNA post-transcriptional modifications. RNA Biol. 2017;14(2):156–63. https://doi.org/10.1080/15476286.2016.1267096.
He C, Huang ZS, Yu CC, et al. Epigenetic regulation of amyloid-beta metabolism in Alzheimer's disease. Curr Med Sci. 2020;40(6):1022–30. https://doi.org/10.1007/s11596-020-2283-0.
Chen D, Cheung H, Lau HC, et al. N (6)-Methyladenosine RNA-binding protein YTHDF1 in gastrointestinal cancers: function, molecular mechanism and clinical implication. Cancers (Basel). 2022;14(14). https://doi.org/10.3390/cancers14143489.
Widagdo J, Anggono V, Wong JJ. The multifaceted effects of YTHDC1-mediated nuclear m (6) a recognition. Trends Genet. 2022;38(4):325–32. https://doi.org/10.1016/j.tig.2021.11.005.
Jiang X, Liu B, Nie Z, et al. The role of m6A modification in the biological functions and diseases. Signal Transduct Target Ther. 2021;6(1):74. https://doi.org/10.1038/s41392-020-00450-x.
Lan Q, Liu PY, Bell JL, et al. The emerging roles of RNA m (6) a methylation and demethylation as critical regulators of tumorigenesis, drug sensitivity, and resistance. Cancer Res. 2021;81(13):3431–40. https://doi.org/10.1158/0008-5472.can-20-4107.
Ma L, Chen T, Zhang X, et al. The m (6) a reader YTHDC2 inhibits lung adenocarcinoma tumorigenesis by suppressing SLC7A11-dependent antioxidant function. Redox Biol. 2021;38:101801. https://doi.org/10.1016/j.redox.2020.101801.
Hsu PJ, Zhu Y, Ma H, et al. Ythdc2 is an N (6)-methyladenosine binding protein that regulates mammalian spermatogenesis. Cell Res. 2017;27(9):1115–27. https://doi.org/10.1038/cr.2017.99.
Ma L, Zhang X, Yu K, et al. Targeting SLC3A2 subunit of system X(C)(−) is essential for m (6) a reader YTHDC2 to be an endogenous ferroptosis inducer in lung adenocarcinoma. Free Radic Biol Med. 2021;168:25–43. https://doi.org/10.1016/j.freeradbiomed.2021.03.023.
Chang G, Shi L, Ye Y, et al. YTHDF3 induces the translation of m (6) A-enriched gene transcripts to promote breast cancer brain metastasis. Cancer Cell. 2020;38(6):857–871.e7. https://doi.org/10.1016/j.ccell.2020.10.004.
Ni W, Yao S, Zhou Y, et al. Long noncoding RNA GAS5 inhibits progression of colorectal cancer by interacting with and triggering YAP phosphorylation and degradation and is negatively regulated by the m (6) a reader YTHDF3. Mol Cancer. 2019;18(1):143. https://doi.org/10.1186/s12943-019-1079-y.
Shi H, Wang X, Lu Z, et al. YTHDF3 facilitates translation and decay of N (6)-methyladenosine-modified RNA. Cell Res. 2017;27(3):315–28. https://doi.org/10.1038/cr.2017.15.
Shi Y, Fan S, Wu M, et al. YTHDF1 links hypoxia adaptation and non-small cell lung cancer progression. Nat Commun. 2019;10(1):4892. https://doi.org/10.1038/s41467-019-12801-6.
Pi J, Wang W, Ji M, et al. YTHDF1 promotes gastric carcinogenesis by controlling translation of FZD7. Cancer Res. 2021;81(10):2651–65. https://doi.org/10.1158/0008-5472.can-20-0066.
Han D, Liu J, Chen C, et al. Anti-tumour immunity controlled through mRNA m (6) a methylation and YTHDF1 in dendritic cells. Nature. 2019;566(7743):270–4. https://doi.org/10.1038/s41586-019-0916-x.
Shi H, Zhang X, Weng YL, et al. M (6) a facilitates hippocampus-dependent learning and memory through YTHDF1. Nature. 2018;563(7730):249–53. https://doi.org/10.1038/s41586-018-0666-1.
Lin X, Chai G, Wu Y, et al. RNA m (6) a methylation regulates the epithelial mesenchymal transition of cancer cells and translation of snail. Nat Commun. 2019;10(1):2065. https://doi.org/10.1038/s41467-019-09865-9.
Wang X, Zhao BS, Roundtree IA, et al. N (6)-methyladenosine modulates messenger RNA translation efficiency. Cell. 2015;161(6):1388–99. https://doi.org/10.1016/j.cell.2015.05.014.
Bokar JA, Shambaugh ME, Polayes D, et al. Purification and cDNA cloning of the AdoMet-binding subunit of the human mRNA (N6-adenosine)-methyltransferase. RNA. 1997;3(11):1233–47.
Liu J, Yue Y, Han D, et al. A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation. Nat Chem Biol. 2014;10(2):93–5. https://doi.org/10.1038/nchembio.1432.
Agarwala SD, Blitzblau HG, Hochwagen A, et al. RNA methylation by the MIS complex regulates a cell fate decision in yeast. PLoS Genet. 2012;8(6):e1002732. https://doi.org/10.1371/journal.pgen.1002732.
Schwartz S, Mumbach MR, Jovanovic M, et al. Perturbation of m6A writers reveals two distinct classes of mRNA methylation at internal and 5′ sites. Cell Rep. 2014;8(1):284–96. https://doi.org/10.1016/j.celrep.2014.05.048.
Pendleton KE, Chen B, Liu K, et al. The U6 snRNA m (6) a methyltransferase METTL16 regulates SAM Synthetase intron retention. Cell. 2017;169(5):824–835.e14. https://doi.org/10.1016/j.cell.2017.05.003.
Patil DP, Chen CK, Pickering BF, et al. M (6) a RNA methylation promotes XIST-mediated transcriptional repression. Nature. 2016;537(7620):369–73. https://doi.org/10.1038/nature19342.
Wen J, Lv R, Ma H, et al. Zc3h13 regulates nuclear RNA m (6) a methylation and mouse embryonic stem cell self-renewal. Mol Cell. 2018;69(6):1028–1038.e6. https://doi.org/10.1016/j.molcel.2018.02.015.
Jia G, Fu Y, Zhao X, et al. N6-methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO. Nat Chem Biol. 2011;7(12):885–7. https://doi.org/10.1038/nchembio.687.
Zheng G, Dahl JA, Niu Y, et al. ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility. Mol Cell. 2013;49(1):18–29. https://doi.org/10.1016/j.molcel.2012.10.015.
Alarcón CR, Goodarzi H, Lee H, et al. HNRNPA2B1 is a mediator of m (6) A-dependent nuclear RNA processing events. Cell. 2015;162(6):1299–308. https://doi.org/10.1016/j.cell.2015.08.011.
Huang H, Weng H, Sun W, et al. Recognition of RNA N (6)-methyladenosine by IGF2BP proteins enhances mRNA stability and translation. Nat Cell Biol. 2018;20(3):285–95. https://doi.org/10.1038/s41556-018-0045-z.
Du H, Zhao Y, He J, et al. YTHDF2 destabilizes m (6) A-containing RNA through direct recruitment of the CCR4-NOT deadenylase complex. Nat Commun. 2016;7:12626. https://doi.org/10.1038/ncomms12626.
Sun T, Wu R, Ming L. The role of m6A RNA methylation in cancer. Biomed Pharmacother. 2019;112:108613. https://doi.org/10.1016/j.biopha.2019.108613.
Chen M, Wong CM. The emerging roles of N6-methyladenosine (m6A) deregulation in liver carcinogenesis. Mol Cancer. 2020;19(1):44. https://doi.org/10.1186/s12943-020-01172-y.
Ma S, Chen C, Ji X, et al. The interplay between m6A RNA methylation and noncoding RNA in cancer. J Hematol Oncol. 2019;12(1):121. https://doi.org/10.1186/s13045-019-0805-7.
Ma Z, Ji J. N6-methyladenosine (m6A) RNA modification in cancer stem cells. Stem Cells. 2020. https://doi.org/10.1002/stem.3279.
Zhang B, Jiang H, Dong Z, et al. The critical roles of m6A modification in metabolic abnormality and cardiovascular diseases. Genes Dis. 2021;8(6):746–58. https://doi.org/10.1016/j.gendis.2020.07.011.
An Y, Duan H. The role of m6A RNA methylation in cancer metabolism. Mol Cancer. 2022;21(1):14. https://doi.org/10.1186/s12943-022-01500-4.
Zhuang M, Li X, Zhu J, et al. The m6A reader YTHDF1 regulates axon guidance through translational control of Robo3.1 expression. Nucleic Acids Res. 2019;47(9):4765–77. https://doi.org/10.1093/nar/gkz157.
Nettersheim D, Berger D, Jostes S, et al. N6-Methyladenosine detected in RNA of testicular germ cell tumors is controlled by METTL3, ALKBH5, YTHDC1/F1/F2, and HNRNPC as writers, erasers, and readers. Andrology. 2019;7(4):498–506. https://doi.org/10.1111/andr.12612.
Jin D, Guo J, Wu Y, et al. M (6) a mRNA methylation initiated by METTL3 directly promotes YAP translation and increases YAP activity by regulating the MALAT1-miR-1914-3p-YAP axis to induce NSCLC drug resistance and metastasis. J Hematol Oncol. 2019;12(1):135. https://doi.org/10.1186/s13045-019-0830-6.
Wu R, Liu Y, Zhao Y, et al. M (6) a methylation controls pluripotency of porcine induced pluripotent stem cells by targeting SOCS3/JAK2/STAT3 pathway in a YTHDF1/YTHDF2-orchestrated manner. Cell Death Dis. 2019;10(3):171. https://doi.org/10.1038/s41419-019-1417-4.
Jin H, Ying X, Que B, et al. N (6)-methyladenosine modification of ITGA6 mRNA promotes the development and progression of bladder cancer. EBioMedicine. 2019;47:195–207. https://doi.org/10.1016/j.ebiom.2019.07.068.
Zhao W, Cui Y, Liu L, et al. METTL3 facilitates Oral squamous cell carcinoma tumorigenesis by enhancing c-Myc stability via YTHDF1-mediated m (6) a modification. Mol Ther Nucleic Acids. 2020;20:1–12. https://doi.org/10.1016/j.omtn.2020.01.033.
Wang Q, Guo X, Li L, et al. N (6)-methyladenosine METTL3 promotes cervical cancer tumorigenesis and Warburg effect through YTHDF1/HK2 modification. Cell Death Dis. 2020;11(10):911. https://doi.org/10.1038/s41419-020-03071-y.
Li Z, Peng Y, Li J, et al. N (6)-methyladenosine regulates glycolysis of cancer cells through PDK4. Nat Commun. 2020;11(1):2578. https://doi.org/10.1038/s41467-020-16306-5.
Zhou J, Xiao D, Qiu T, et al. Loading MicroRNA-376c in extracellular vesicles inhibits properties of non-small cell lung Cancer cells by targeting YTHDF1. Technol Cancer Res Treat. 2020;19:1533033820977525. https://doi.org/10.1177/1533033820977525.
Li Q, Ni Y, Zhang L, et al. HIF-1α-induced expression of m6A reader YTHDF1 drives hypoxia-induced autophagy and malignancy of hepatocellular carcinoma by promoting ATG2A and ATG14 translation. Signal Transduct Target Ther. 2021;6(1):76. https://doi.org/10.1038/s41392-020-00453-8.
Bai X, Huang Y, Huang W, et al. Wnt3a/YTHDF1 regulated Oxaliplatin-induced neuropathic pain via TNF-α/IL-18 expression in the spinal cord. Cell Mol Neurobiol. 2022. https://doi.org/10.1007/s10571-022-01267-8.
Nishizawa Y, Konno M, Asai A, et al. Oncogene c-Myc promotes epitranscriptome m (6) a reader YTHDF1 expression in colorectal cancer. Oncotarget. 2018;9(7):7476–86. https://doi.org/10.18632/oncotarget.23554.
Zheng L, Tang X, Lu M, et al. microRNA-421-3p prevents inflammatory response in cerebral ischemia/reperfusion injury through targeting m6A reader YTHDF1 to inhibit p65 mRNA translation. Int Immunopharmacol. 2020;88:106937. https://doi.org/10.1016/j.intimp.2020.106937.
Xu C, Yuan B, He T, et al. Prognostic values of YTHDF1 regulated negatively by mir-3436 in glioma. J Cell Mol Med. 2020;24(13):7538–49. https://doi.org/10.1111/jcmm.15382.
Zhang RN, Wu DM, Wu LP, et al. LncRNA LINC00337 sponges mir-1285-3p to promote proliferation and metastasis of lung adenocarcinoma cells by upregulating YTHDF1. Cancer Cell Int. 2021;21(1):550. https://doi.org/10.1186/s12935-021-02253-8.
Chi F, Cao Y, Chen Y. Analysis and validation of circRNA-miRNA network in regulating m (6) a RNA methylation modulators reveals CircMAP2K4/miR-139-5p/YTHDF1 Axis involving the proliferation of hepatocellular carcinoma. Front Oncol. 2021;11:560506. https://doi.org/10.3389/fonc.2021.560506.
Wang S, Zhang J, Wu X, et al. Differential roles of YTHDF1 and YTHDF3 in embryonic stem cell-derived cardiomyocyte differentiation. RNA Biol. 2021;18(9):1354–63. https://doi.org/10.1080/15476286.2020.1850628.
Jiang D, Hou J, Qian Y, et al. YTHDF1-regulated expression of TEAD1 contributes to the maintenance of intestinal stem cells. Biochem Biophys Res Commun. 2021;557:85–9. https://doi.org/10.1016/j.bbrc.2021.03.175.
Han B, Yan S, Wei S, et al. YTHDF1-mediated translation amplifies Wnt-driven intestinal stemness. EMBO Rep. 2020;21(4):e49229. https://doi.org/10.15252/embr.201949229.
Liu T, Zheng X, Wang C, et al. The m (6) a “reader” YTHDF1 promotes osteogenesis of bone marrow mesenchymal stem cells through translational control of ZNF839. Cell Death Dis. 2021;12(11):1078. https://doi.org/10.1038/s41419-021-04312-4.
Zhao T, Zhao R, Yi X, et al. METTL3 promotes proliferation and myogenic differentiation through m (6) a RNA methylation/YTHDF1/2 signaling axis in myoblasts. Life Sci. 2022;298:120496. https://doi.org/10.1016/j.lfs.2022.120496.
Hu L, Wang J, Huang H, et al. YTHDF1 regulates pulmonary hypertension through translational control of MAGED1. Am J Respir Crit Care Med. 2021;203(9):1158–72. https://doi.org/10.1164/rccm.202009-3419OC.
Lein ES, Hawrylycz MJ, Ao N, et al. Genome-wide atlas of gene expression in the adult mouse brain. Nature. 2007;445(7124):168–76. https://doi.org/10.1038/nature05453.
Yu J, She Y, Yang L, et al. The m (6) a readers YTHDF1 and YTHDF2 synergistically control cerebellar parallel Fiber growth by regulating local translation of the key Wnt5a signaling components in axons. Adv Sci (Weinh). 2021;8(22):e2101329. https://doi.org/10.1002/advs.202101329.
Weng YL, Wang X, An R, et al. Epitranscriptomic m (6) a regulation of axon regeneration in the adult mammalian nervous system. Neuron. 2018;97(2):313–325.e6. https://doi.org/10.1016/j.neuron.2017.12.036.
Xing Y, Cheng D, Shi C, et al. The protective role of YTHDF1-knock down macrophages on the immune paralysis of severe sepsis rats with ECMO. Microvasc Res. 2021;137:104178. https://doi.org/10.1016/j.mvr.2021.104178.
Li Z, Teng M, Jiang Y, et al. YTHDF1 negatively regulates Treponema pallidum-induced inflammation in THP-1 macrophages by promoting SOCS3 translation in an m6A-dependent manner. Front Immunol. 2022;13:857727. https://doi.org/10.3389/fimmu.2022.857727.
Wang Y, Yu Z, Shi W, et al. HLA complex P5 upregulation is correlated with poor prognosis and tumor progression in esophageal squamous cell carcinoma. Bioengineered. 2022;13(4):9301–11. https://doi.org/10.1080/21655979.2022.2051854.
Zhao F, Ge F, Xie M, et al. FTO mediated ERBB2 demethylation promotes tumor progression in esophageal squamous cell carcinoma cells. Clin Exp Metastasis. 2022;39(4):623–39. https://doi.org/10.1007/s10585-022-10169-4.
Chen XY, Liang R, Yi YC, et al. The m (6) a reader YTHDF1 facilitates the tumorigenesis and metastasis of gastric Cancer via USP14 translation in an m (6) A-dependent manner. Front Cell Dev Biol. 2021;9:647702. https://doi.org/10.3389/fcell.2021.647702.
Li H, Wang C, Lan L, et al. METTL3 promotes oxaliplatin resistance of gastric cancer CD133+ stem cells by promoting PARP1 mRNA stability. Cell Mol Life Sci. 2022;79(3):135. https://doi.org/10.1007/s00018-022-04129-0.
Bai Y, Yang C, Wu R, et al. YTHDF1 regulates Tumorigenicity and Cancer stem cell-like activity in human colorectal carcinoma. Front Oncol. 2019;9:332. https://doi.org/10.3389/fonc.2019.00332.
Chen P, Liu XQ, Lin X, et al. Targeting YTHDF1 effectively re-sensitizes cisplatin-resistant colon cancer cells by modulating GLS-mediated glutamine metabolism. Mol Ther Oncolytics. 2021;20:228–39. https://doi.org/10.1016/j.omto.2021.01.001.
Tian J, Ying P, Ke J, et al. ANKLE1 N (6) -Methyladenosine-related variant is associated with colorectal cancer risk by maintaining the genomic stability. Int J Cancer. 2020;146(12):3281–93. https://doi.org/10.1002/ijc.32677.
Orouji E, Peitsch WK, Orouji A, et al. Oncogenic role of an epigenetic reader of m (6) a RNA modification: YTHDF1 in Merkel cell carcinoma. Cancers (Basel). 2020;12(1). https://doi.org/10.3390/cancers12010202.
Bian S, Ni W, Zhu M, et al. Identification and validation of the N6-Methyladenosine RNA methylation regulator YTHDF1 as a novel prognostic marker and potential target for hepatocellular carcinoma. Front Mol Biosci. 2020;7:604766. https://doi.org/10.3389/fmolb.2020.604766.
Jin D, Guo J, Wu Y, et al. M (6) a demethylase ALKBH5 inhibits tumor growth and metastasis by reducing YTHDFs-mediated YAP expression and inhibiting miR-107/LATS2-mediated YAP activity in NSCLC. Mol Cancer. 2020;19(1):40. https://doi.org/10.1186/s12943-020-01161-1.
Liu H, Xu Y, Yao B, et al. A novel N6-methyladenosine (m6A)-dependent fate decision for the lncRNA THOR. Cell Death Dis. 2020;11(8):613. https://doi.org/10.1038/s41419-020-02833-y.
Sun Z, Su Z, Zhou Z, et al. RNA demethylase ALKBH5 inhibits TGF-β-induced EMT by regulating TGF-β/SMAD signaling in non-small cell lung cancer. FASEB J. 2022;36(5):e22283. https://doi.org/10.1096/fj.202200005RR.
Li X, Li N, Huang L, et al. Is hydrogen sulfide a concern during treatment of lung adenocarcinoma with ammonium Tetrathiomolybdate? Front Oncol. 2020;10:234. https://doi.org/10.3389/fonc.2020.00234.
Yang F, Jin H, Que B, et al. Dynamic m (6) a mRNA methylation reveals the role of METTL3-m (6) A-CDCP1 signaling axis in chemical carcinogenesis. Oncogene. 2019;38(24):4755–72. https://doi.org/10.1038/s41388-019-0755-0.
Liu T, Wei Q, Jin J, et al. The m6A reader YTHDF1 promotes ovarian cancer progression via augmenting EIF3C translation. Nucleic Acids Res. 2020;48(7):3816–31. https://doi.org/10.1093/nar/gkaa048.
Hao L, Wang JM, Liu BQ, et al. m6A-YTHDF1-mediated TRIM29 upregulation facilitates the stem cell-like phenotype of cisplatin-resistant ovarian cancer cells. Biochim Biophys Acta Mol Cell Res. 2021;1868(1):118878. https://doi.org/10.1016/j.bbamcr.2020.118878.
Yao X, Li W, Li L, et al. YTHDF1 upregulation mediates hypoxia-dependent breast cancer growth and metastasis through regulating PKM2 to affect glycolysis. Cell Death Dis. 2022;13(3):258. https://doi.org/10.1038/s41419-022-04711-1.
Chen H, Yu Y, Yang M, et al. YTHDF1 promotes breast cancer progression by facilitating FOXM1 translation in an m6A-dependent manner. Cell Biosci. 2022;12(1):19. https://doi.org/10.1186/s13578-022-00759-w.
Wei K, Gao Y, Wang B, et al. Methylation recognition protein YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) regulates the proliferation, migration and invasion of osteosarcoma by regulating m6A level of CCR4-NOT transcription complex subunit 7 (CNOT7). Bioengineered. 2022;13(3):5236–50. https://doi.org/10.1080/21655979.2022.2037381.
Yuan Y, Yan G, He M, et al. ALKBH5 suppresses tumor progression via an m (6) A-dependent epigenetic silencing of pre-miR-181b-1/YAP signaling axis in osteosarcoma. Cell Death Dis. 2021;12(1):60. https://doi.org/10.1038/s41419-020-03315-x.
Liu XS, Kui XY, Gao Y, et al. Comprehensive analysis of YTHDF1 immune infiltrates and ceRNA in human esophageal carcinoma. Front Genet. 2022;13:835265. https://doi.org/10.3389/fgene.2022.835265.
Wang S, Gao S, Zeng Y, et al. N6-Methyladenosine reader YTHDF1 promotes ARHGEF2 translation and RhoA signaling in colorectal Cancer. Gastroenterology. 2022;162(4):1183–96. https://doi.org/10.1053/j.gastro.2021.12.269.
Yarmishyn AA, Yang YP, Lu KH, et al. Musashi-1 promotes cancer stem cell properties of glioblastoma cells via upregulation of YTHDF1. Cancer Cell Int. 2020;20(1):597. https://doi.org/10.1186/s12935-020-01696-9.
Li W, Chen G, Feng Z, et al. YTHDF1 promotes the proliferation, migration, and invasion of prostate cancer cells by regulating TRIM44. Genes Genomics. 2021;43(12):1413–21. https://doi.org/10.1007/s13258-021-01175-z.
Wu Q, Xie X, Huang Y, et al. N6-methyladenosine RNA methylation regulators contribute to the progression of prostate cancer. J Cancer. 2021;12(3):682–92. https://doi.org/10.7150/jca.46379.
Geng Y, Guan R, Hong W, et al. Identification of m6A-related genes and m6A RNA methylation regulators in pancreatic cancer and their association with survival. Ann Transl Med. 2020;8(6):387. https://doi.org/10.21037/atm.2020.03.98.
Huang R, Yang L, Zhang Z, et al. RNA m (6) a demethylase ALKBH5 protects against pancreatic ductal adenocarcinoma via targeting regulators of Iron metabolism. Front Cell Dev Biol. 2021;9:724282. https://doi.org/10.3389/fcell.2021.724282.
Pan J, Xu L, Pan H. Development and validation of an m6A RNA methylation regulator-based signature for prognostic prediction in cervical squamous cell carcinoma. Front Oncol. 2020;10:1444. https://doi.org/10.3389/fonc.2020.01444.
Liu T, Li C, Jin L, et al. The prognostic value of m6A RNA methylation regulators in Colon adenocarcinoma. Med Sci Monit. 2019;25:9435–45. https://doi.org/10.12659/msm.920381.
Anita R, Paramasivam A, Priyadharsini JV, et al. The m6A readers YTHDF1 and YTHDF3 aberrations associated with metastasis and predict poor prognosis in breast cancer patients. Am J Cancer Res. 2020;10(8):2546–54.
Kim CG, Kim C, Yoon SE, et al. Hyperprogressive disease during PD-1 blockade in patients with advanced hepatocellular carcinoma. J Hepatol. 2021;74(2):350–9. https://doi.org/10.1016/j.jhep.2020.08.010.
Acknowledgements
Not applicable.
Funding
This study was supported by Kunming Science and Technology Plan Project (grant NO. 2020–1-H-003). The First People’s Hospital of Yunnan Province Clinical Medicine Center Opening Project (grant NO.2022LCZXKF-XZ01).
Author information
Authors and Affiliations
Contributions
Wenjun Ren, Yixiao Yuan and Yongwu Li collected the related literature. Xiulin Jiang, Jun Peng and Luciano Mutti wrote the manuscript and revised the manuscript. All authors have read and approved the final manuscript.
Corresponding authors
Ethics declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.
About this article
Cite this article
Ren, W., Yuan, Y., Li, Y. et al. The function and clinical implication of YTHDF1 in the human system development and cancer. Biomark Res 11, 5 (2023). https://doi.org/10.1186/s40364-023-00452-1
Received:
Accepted:
Published:
DOI: https://doi.org/10.1186/s40364-023-00452-1