Abstract
The Cyclin-dependent kinase (CDK) class of serine/threonine kinases has crucial roles in the regulation of cell cycle transition and is mainly involved in the pathogenesis of cancers. The expression of CDKs is controlled by a complex regulatory network comprised of genetic and epigenetic mechanisms, which are dysregulated during the progression of cancer. The abnormal activation of CDKs results in uncontrolled cancer cell proliferation and the induction of cancer stem cell characteristics. The levels of CDKs can be utilized to predict the prognosis and treatment response of cancer patients, and further understanding of the function and underlying mechanisms of CDKs in human tumors would pave the way for future cancer therapies that effectively target CDKs. Defects in the regulation of cell cycle and mutations in the genes coding cell-cycle regulatory proteins lead to unrestrained proliferation of cells leading to formation of tumors. A number of treatment modalities have been designed to combat dysregulation of cell cycle through affecting expression or activity of CDKs. However, effective application of these methods in the clinical settings requires recognition of the role of CDKs in the progression of each type of cancer, their partners, their interactions with signaling pathways and the effects of suppression of these kinases on malignant features. Thus, we designed this literature search to summarize these findings at cellular level, as well as in vivo and clinical levels.
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Introduction
Cyclin-dependent kinases (CDKs) are a group of serine/threonine kinases with crucial roles in the regulation of cell cycle progression. The activity of these kinases is induced by cyclins. In fact, CDK/cyclin complexes control progression of the cell cycle in an orderly manner [1]. Emerging evidence suggest that CDKs and cyclins actively participate in the regulation of transcription, epigenetic mechanisms, metabolic processes and self-renewal capacity of stem cells [1]. Most notably, some of these functions are exerted in an independent manner from establishment of CDKs/cyclins complexes [1]. Another group of proteins, namely cyclin-dependent kinase inhibitors (CKIs) has been revealed to negatively regulate cyclin/CDKs. The main function of CDKIs is to obstruct cell cycle transition and suppress cell proliferation through inhibition of the enzymatic activity of CDKs. Inhibitor of CDK4 proteins and CDK-interacting protein/kinase inhibitory proteins belong to this group [2].
Defects in the regulation of cell cycle and mutations in the genes coding cell-cycle regulatory proteins result in unrestrained proliferation of cells leading to formation of tumors [3, 4]. Accordingly, modulation of activity of these proteins by therapeutic agents has been suggested as a promising strategy for treatment of cancers [5]. Successful introduction of these modalities into clinical settings needs proper recognition of the role of CDKs in the progression of each type of cancer, their interacting molecules and signaling pathways and the effects of suppression of these kinases on malignant features. Thus, we designed this literature search to summarize these findings at cellular level, as well as in vivo and clinical levels.
Cyclin-dependent kinase 1 (CDK1)
Cell line studies
A recent study has demonstrated that vitro that centromere protein F (CENPF) through interaction with CDK1 can increase G2/M-phase transition, enhance cell proliferation and possibly activate the anti-tumor effects of p53 in a human adrenocortical carcinoma cell line. Moreover, assessment of GSEA has verified involvement of CENPF in the G2/M-phase cell cycle and p53 signaling [6].
Expression of CDK1 has also been found to be increased in bladder cancer cells, parallel with over-expression of the long non-coding RNA (lncRNA) PVT1. Notably, suppression of PVT1 has decreased activity, proliferative potential, colony formation, migratory capacity, and invasiveness of bladder cancer cells. miR-31 binding sites have been reported in both PVT1 and CDK1 transcripts. Taken together, PVT1-mediated reduction of miR-31 could increase expression of CDK1 in bladder cancer cells to enhance their proliferative potential, migration, and invasion [7]. Another study has shown the role of CDK1 in phosphorylation of TFCP2L1 at Thr177 in embryonic stem cells of mice as well as human bladder cancer cells. Notably, this type of phosphorylation has a crucial role in pluripotency and cell cycle progression of stem cells through modulation of expression of developmental genes. CDK1/TFCP2L1 axis is also involved in the induction of stemness characteristics and tumorigenic ability of bladder cancer cells [8]. Treatment of bladder cancer cells with the protein kinase D (PKD) inhibitor CRT0066101 has suppressed proliferation of these cells. CRT0066101 treatment or PKD2 silencing has induced cell cycle arrest at the G2/M phase, diminished expressions of cyclin B1, CDK1 and levels of CDK1 phosphorylated at Thr161, while increasing p27Kip1 and CDK1 phosphorylated at Thr14/Tyr15. This protein kinase inhibitor has also decreased expression of Cdc25C, which dephosphorylates and induces activity of CDK1, while enhancing function of Chk1, which suppresses CDK1 activity through phosphorylation and inactivation of Cdc25C. Moreover, CRT0066101 could elevate expression of a number of proteins that inhibit activity of the CDK1/cyclin B1 complex [9].
In breast cancer cells, the RNA binding protein KIAA1429 has been shown to interact with CDK1. Although this RNA binding protein is regarded as an N6-methyladenosine-associated regulatory protein, its oncogenic roles in breast cancer are exerted through regulation of CDK1 in an independent manner from its association with N6-methyladenosine (Fig. 1). Treatment of breast cancer cells with 5′-fluorouracil has efficiently reduced expressions of KIAA1429 and CDK1 [10]. Furthermore, siRNA-mediated silencing of CDK1 and CDC20 has significantly repressed cell migration and invasion of two breast cancer cell lines [11]. Another study has shown that knockdown of the ubiquitin-associated domain-containing gene UBAP2L in breast cancer cells suppresses their proliferation, impairs their colony formation aptitude and induces cell cycle arrest at G2/M phase. Most notably, this intervention has led to enhancement of p21 levels, while reducing levels of both CDK1 and Cyclin B1 [12].
A schematic diagram of CDK1 and the role of WTAP in modulating CDK2 in renal cell carcinoma. Mounting evidence has demonstrated the roles of N6-methyladenosine (m6A) in physiological processes and the progression of various human cancers such as cell cycle regulation that is mostly dependent on cyclins and CDKs. As a component in the m6A ‘writers’, WTAP is detected to be an RNA-binding protein and has a role in the m6A modification, mRNA splicing as well as processing. As an illustration, a recent study has detected that WTAP, an important component of the m6A writer complex, could have an oncogenic role in renal cell carcinoma tumorigenesis via physically binding to CDK2 transcript and promoting its transcript stability [68]
Cyclin B/CDK1 has been shown to phosphorylate inhibitor of apoptosis stimulating protein of P53 (iASPP), thus increasing nuclear localization of this protein and its inhibitory effects on p53. In Burkitt lymphoma cells, iASPP has been found to affect activity of transactivation domain p63 (TAp63). In fact, the interplay between CDK1 and iASPP can enhance the suppressive impact of iASPP on p53 and TAp63. Most notably, the tumor suppressor miR-129 has been shown to suppress expression of CDK1 and iASPP through binding with their transcripts. Moreover, CDK1 targeting by miR-129 can lead to inhibition of iASPP phosphorylation, therefore deterring nuclear localization of iASPP and its suppressive impact on p53 and TAp63 [13].
The oncogenic mutation HRASV12 has been found to induce activity of CDK1 and enhance protein O-GlcNAcylation, both of them having essential roles in induction of SOX2 expression and cancer stem cell properties in fibroblasts and cancer cell lines harboring RAS mutations. Most notably, the CDK inhibitor dinaciclib could reduce the quantities of cancer stem cells originated from these cells [14].
In colorectal cancer cells, knock-down of CDK1 has induced sensitivity to apoptosis. Moreover, CDK1 targeting with a MEK/ERK inhibitor has demonstrated effective impacts on proliferative abilities of these cells [15].
Notably, experiments in the vemurafenib-resistant colon cancer sublines have shown stable activation of CDK1, signifying the role of CDK1 activation in stimulation of resistance to vemurafenib. Adefovir dipivoxil that interrupts the interaction between CDK1 and KCTD12 and induces cell cycle arrest at G2 could inhibit colon cancer cells proliferation and induce sensitivity to vemurafenib [16]. Table 1 shows function of CDKs in cancer cell lines.
Animal studies
In vivo assessments have shown that down-regulation of miR-31 enhances expression of CDK1 at transcript and protein levels. Down-regulation of PVT1 (an lncRNA which increases expression of CDK1) has led to lessening of bladder tumor size, decrease in the proliferation rate of tumor cells and reduction of CDK1 and Ki-67-expressing cells as demonstrated by immunohistochemistry [7]. In animal models of breast cancer, up-regulation of RBM7 which induces activity of CDK1 has been shown to increase tumor growth [19]. In colorectal cancer, high levels of miR-378a-5p reduces tumor burden through decreasing expression of CDK1 [24]. Moreover, disruption of the interaction between CDK1 and KCTD12 using Adefovir dipivoxil has been shown to reduce in vivo tumorigenesis of colon cancer cells and induce vemurafenib sensitivity in xenografts [16].
Most notably, in animal models of hepatocellular carcinoma, administration of a CDK1 inhibitor along with sorafenib has enhanced the effectiveness of sorafenib [37]. Moreover, in animal models of pancreatic cancer, reduction of phosphorylation of CDK1, 2, 7, and 9 by AT7519 has been associated with reduction of tumor growth [63]. Studies in animal models of other cancers have also verified that decrease in activity of CDKs consistently reduces tumor burden and induces sensitivity to available therapies (Table 2).
Investigations in clinical samples
The CDK1-interacting protein CENPF has been found to be over-expressed in human adrenocortical carcinoma samples in correlation with tumor stage and poor overall survival (OS). Further assessment of immune cells infiltration has shown that over-expression of CENPF is associated with different pattern of infiltration of immune cells and high TMB/MSI score. Based on the results of gene-drug interaction assessments inhibitors of this protein, such as Cisplatin, Sunitinib, and Etoposide, can be putative therapeutic modalities for adrenocortical carcinoma [6]. In clinical samples of bladder cancer, activity of the CDK1/TFCP2L1 axis has been found to be associated with aggressive characteristics of tumors including advanced tumor grade, lymphovascular/muscularis-propria invasion, metastatic ability and poor clinical outcomes [8].
Assessment of expression profiles of three breast cancer datasets has led to identification of hub genes that indicate poor prognosis. Further analyses have indicated enrichment of four up-regulated genes, namely CDK1, CDC20, AURKA, and MCM4 in oocyte meiosis and cell cycle pathways. Taken together, bioinformatics methods and experimental validation have suggested these genes as reliable markers for breast cancer [11]. In breast cancer, up-regulation of CDK1 has been associated with short overall, relapse-free and progression-free survival times as well as advanced clinical stage [69]. In patients with cholangiocarcinoma, up-regulation of CDK1 or PSMC2 (which regulates CDK1) has been associated with lymph node metastasis and advanced clinical stage [22] and tumor grade [23], respectively. Table 3 shows the association between dysregulation of CDKs in clinical samples and clinical characteristics.
Cyclin-dependent kinase 2 (CDK2)
Cell line studies
Inactivation of CDK2 has been shown to effectively overcome the differentiation arrest of acute myeloid leukemia (AML) cells. Treatment of AML cells with CDK2-targeted proteolysis-targeting chimeras (PROTACs) has resulted in prompt and effective degradation of CDK2 in various cell lines without similar destruction of other targets. Moreover, this therapeutic agent has induced significant differentiation of AML cells as well as primary patient cells [92]. Another study in AML cells has shown that CDK2 is the only interphase CDK that is degraded through a ubiquitin-dependent proteasomal system. This mode of degradation of CDK2 is associated differentiation of AML cells. KLHL6 has been shown to be the specific E3 ubiquitin ligase which regulates CDK2 degradation. Notably, suppression of CDK2, but not CDK1/4/6, could induce granulocytic differentiation in AML cell lines. From a mechanistical point of view, CDK2 depletion results in reactivation of translation of differentiation pathway. Moreover, the effect of CDK2 in induction of differentiation blockade is exerted through preserving the activity of PRDX2 [93]. Moreover, CDK2 has been shown to down-regulate expression of C/EBPα through ubiquitin-dependent proteasomal degradation system resulting in differentiation blockade in AML. Mechanistically, CDK2-induced C/EBPα down-regulation is facilitated by SKP2. In fact, CDK2 enhances stability of SKP2 through Ser64 phosphorylation leading to C/EBPα ubiquitination. Suppression of CDK2 results in down-regulation of SKP2 and up-regulation of C/EBPα in myeloid cells. Cumulatively, CDK2-SKP2 axis has been identified as a therapeutic target for AML [94]. Another study has shown that GSK8612-mediated TBK1 inhibition and si-TBK1 can regulate CDK2 expression in AML cells through AKT pathway. Suppression of activity of AKT can enhance sensitivity of AML cells to daunorubicin, endorsing the interaction between TBK1 and the AKT/CDK2 axis [95].
Treatment of bladder cancer cells with propofol could inhibit their proliferation and enhance cell apoptosis through regulation of CDK2 expression. Mechanistically, propofol up-regulates expression of a CDK2-targeting miRNA, namely miR-340. Suppression of miR-340 has reversed the impacts of propofol on proliferation and apoptosis of bladder cancer cells. Moreover, suppression of CDK2 can partly reverse the impacts of miR-340 inhibition on proliferation and apoptosis of propofol-treated bladder cancer cells [96].
The Cdk4/6 inhibitor palbociclib has been shown to exert antitumor effects against bladder cancer cells through modification of Cdk2. Palbociclib has been shown to induce apoptosis of bladder cancer cells rather than cell cycle arrest. Activation Cdk2 has an indispensable role in palbociclib-induced apoptosis, as depletion of Cdk2 has suppressed caspase-3 activation and apoptosis. Activation Cdk2 has been shown to induce p-Rad9 mitochondrial translocation and its interaction with Bcl-xl, resulting in Bak activation and induction of apoptosis [97].
In breast cancer cells, concurrent administartion of CDK2 and CDK4/6 inhibitiors could reverse palbociclib resistance through increasing cell senescence [98]. Another functional study has shown that CDK2-mediated phosphorylation of EZH2 induces and preserves proliferation of triple-negative breast cancer cells [99]. Table 4 summarizes function of CDK2 in different cancer cell lines. Figure 2 illustrates the interaction between STAT3 signaling pathway and CDK1 and CDK2 in lung cancer (Fig. 3).
A schematic illustration of the role of STAT3 signaling cascade in regulating CDK1 and CDK2 in lung cancer. Accumulating evidence has illustrated that CDK1/GP130/STAT3 signaling could promote lung cancer tumorigenesis. It has been reported that Iron-dependent CDK1 activity could phosphorylate 4E-BP1, which in turn elevates STAT3 signaling pathway via upregulation of GP130 [48]. Moreover, another research has revealed that PROS could downregulate VEGF induced proliferation, migration, and tube formation in non-small lung cancer cells and inhibits angiogenesis in chorioallantoic membrane assay through attenuating phosphorylation of VEGFR2, Src, and STAT3, thereby inducing sub G1 accumulation, S phase arrest [158]
A schematic representation of the role of PI3K/AKT/mTOR and MAPK/ERK signaling pathways in regulating the expression of CDK2 and CDK4/6 in various human cancers
Recent study has detected that upregulation of PTEN and Rb expression levels could lead to promoting sensitivity to CDK4/6 inhibitors, which could in turn result in reducing the expression of AKT and PI3K in ER-Positive Breast Cancer. Whereas, acquired loss of Rb and PTEN expression could induce resistance to CDK4/6 inhibitors in patients, and thereby promoting hyperactivation of CDK2 and CDK4 [172]. Moreover, other finding points out that IGF1R overexpression, as an escape mechanism, could elevate resistance to CDK4/6 inhibitors in Ewing sarcoma. Therefore, dual targeting of CDK4/6 and IGF1R could play an effective role in providing a candidate synergistic combination for clinical application in this disease and promoting inhibition of the cell cycle as well as PI3K/mTOR axis in tumor cells [173]. In addition, a recent clinical study has revealed that suppression of CDK4/6 phosphorylation and the complex with cyclin D as well as downregulating PI3K/AKT/mTOR signaling cascade could remarkably reduce cell viability, induce apoptosis, and promote the percentage of cells in G1 phase in hepatocellular carcinoma [174]. All the information regarding the role of these cascades involved in the regulation of CDK2 and CDK4/6 expression in various types of human cancers can be seen in Tables 4 and 10.
Animal studies
Depletion of CDK2 has led to blockade of AML cells growth in animal models and increased survival of xenograft mice models [93]. Another study in animal models of AML has shown that concomitant administration of chidamide and doxorubicin could inhibit HDAC3-AKT-P21-CDK2 signaling and reduce tumor growth [101].
Another experiment in an animal model of bladder cancer has shown the anticancer role of Cdk2 activation in palbociclib-treated animals, indicating that the anticancer effect of palbociclib is exerted via Cdk2 activation [97]. In xenogaft models of breast cancer, depletion of CDK2 and CDK4/6 has reduced tumor growth and palbociclib resistance [98]. Similar results have been reported in animal models of other types of cancers (Table 5).
Investigations in clinical samples
Up-regulation of CDK2 has been reported in diverse types of cancers. In AML, up-regulation of HDAC3-AKT-P21-CDK2 signaling has been associated with shorter event-free and overall survival (OS) times [101]. In bladder cancer, expression of CDK2 has been increased, while expression of a CDK2-targeting miRNA, namely miR-3619 has been decreased. These observations have been associated with advanced tumor stage and grade [105]. In breast cancer, up-regulation of MTHFD2, which contributes in the cell cycle through binding to CDK2, has been associated with shorter OS, tumor grade and stage [107]. Other studies have shown up-regulation of a number of CDK2-interactiong circRNAs such as hsa_circ_0000520 [128], circ_0084927 [129] and circZFR [130] in cervical cancer patients. Notably, up-regulation of circZFR has been associated with lymphatic metastasis in this type of cancer [130]. Several other studies have found association between dysregulation of CDK2 or its interacting partners and clinical data of patients (Table 6).
Cyclin-dependent kinase 3 (CDK3)
Cell line studies
CDK3 has been shown to participate in regulation of cell cycle transition at G0/G1 and G1/S phases. Up-regulation of CDK3 in breast cancer cells has suppressed their migration and invasion. Further experiments in these cells have identified miR-4469 as a CDK3-targeting miRNA. Consistent with this finding, miR-4469-induced enhancement of cell motility could be obliterated by CDK3 up-regulation. Assessments of RNA-seq data and western blot assay have indicated inhibition of Wnt pathway by CDK3 expression. Besides, Wnt3a treatment could abolish the inhibitory effect of CDK3 in cell motility, indicating the role of CDK3 as an upstream regulator of Wnt signaling in these cells [181].
CDK3 has also been reported to participate in ERα signaling and resistance to tamoxifen. The anti-cancer agent norcantharidin (NCTD) has been found to regulate miR-873/CDK3 axis. Treatment of breast cancer cells with NCTD has led to reduction of transcriptional activity of ERα but not ERβ via influencing activity of miR-873/CDK3 axis. Moreover, NCTD has been shown to inhibit proliferation of breast cancer cells and induce sensitivity to tamoxifen via this axis. Mechanistically, NCTD blocks tamoxifen induced transcriptional activity and ERα downstream gene expression. Moreover, it reestablishes tamoxifen induced recruitment of ERα co-repressors [182]. The CDK3 targeting miRNA, miR‐125a‐3p has also been revealed to inhibit transactivation of ERα and prevail tamoxifen resistance in ER + breast cancer cells [183]. Similarly, miR-873 has been found to regulate transcriptional activity of ERα and resistance to tamoxifen through influencing expression of CDK3 in breast cancer cells [184].
In colorectal cancer cells, Cdk3 has been shown to promote epithelial-mesenchymal transition (EMT) via enhancing activity of AP-1 [185]. Another study in esophageal squamous cell carcinoma cells has shown that the oncogenic circular RNA circRNA_141539 exerts its function through sponging miR-4469 and enhancing activity of CDK3 [186]. Table 7 shows the function of CDK3 based on cell line studies.
Animal studies
While a single study in breast cancer models has shown that up-regulation of CDK3 decreases metastatic abilities of breast cancer cells [181], other studies have shown that up-regulation of CDK3-targeting miRNAs miR-125a-3p [183] and miR-873 [184] leads to reduction of tumor growth. In xenograft models of colorectal cancer, up-regulation of CDK3 has been accompanied by enhancement of metastatic ability of cancer cells [185]. Table 8 summarizes function of CDK3 in animal models of cancer.
Investigations in clinical samples
Expression assays in breast cancer samples have shown that up-regulation of CDK3 is associated with chemoresistance [187]. In colorectal cancer samples, up-regulation of this member of CDK family has been associated with shorter progression-free survival and advanced TMN stage [186]. In clinical samples of nasopharyngeal carcinoma, up-regulation of CDK3 has been associated with tumor infiltration, lymph node metastasis and TNM staging [192]. Table 9 summarizes results of studies that reported association between up-regulation of CDK3 and clinical parameters.
Cyclin-dependent kinase 4/6 (CDK4/6)
Cell line studies
An in vitro study in AML has verified that suppression of CDK4/6 and autophagy enhances apoptosis in t(8; 21) AML cells in a synergic manner [194]. Similarly, CDK4/6 inhibition is a novel therapeutic modality for bladder cancer irrespective of RB1 status [195]. This treatment has reduced FOXM1 phosphorylation and exhibited synergy with cisplatin [195]. Another in vitro study in breast cancer cells has reported loss of the FAT1 as a mechanism for induction of resistance to CDK4/6 inhibitors. Mechanistically, FAT1 silencing has led to suppression of Hippo pathway in ER + cancer cells [196]. Single-cell assessment of CDK2 activity has confirmed difference in cell-cycle regulation between the luminal androgen receptor (LAR) subtype of triple negative breast cancer (TNBC) and basal-like cells. In fact, palbociclib-sensitive LAR cells leave mitotic cycle with low level of CDK2 activity, and enter a quiescent phase that needs activity of CDK4/6 for going back into cell-cycle. On the other hand, palbociclib-resistant basal-like cells leave mitosis and directly enter into a proliferative phase characterized by high level of CDK2 activity, circumventing the constraint point and the need for CDK4/6 activity. CDK4/6 inhibition has synergism with PI3 kinase inhibition in reduction of proliferation of PIK3CA-mutant TNBC cells, indicating that other subtypes of TNBC can be responsive to CDK4/6 inhibitors [197]. In breast and other solid tumors, CDK4/6 inhibitors could trigger anti-tumour immune responses [198]. Moreover, experiments in cervical cancer cells have shown that cyclin D-CDK4/6 inhibition enhances sensitivity of immune-refractory cancers through hindering the SCP3–NANOG axis [199]. Table 10 summarizes function of CDK4/6 based on cell line studies.
Animal studies
Experiments in animal models of AML have verified that CDK4/6 inhibition enhances autophagy. Moreover, concurrent administration CDK4/6 inhibitor and autophagy inhibitor has reduced tumor growth in these models [333]. Similarly, combination of cisplatin and CDK4/6 inhibitors has significantly reduced bladder cancer growth [195]. In xenograft models of breast cancer, CDK4/6 inhibitors could reduce proliferation, and enhance anti-tumor immune responses [198]. In addition, in this type of cancer, combined inhibition of CDK2 and CDK4/6 has enhaced sensitivity to palbociclib [98]. Besides, combination of CDK4/6 inhibitor, abemaciclib, with c-Met/Trk inhibitor, altiratinib has been shown to be effective against glioma-initiating cells [256]. Table 11 shows function of CDK4/6 in animal models of cancer.
Investigations in clinical samples
Investigations in breast cancer samples have shown up-regulation of CDK4/6 in different subtypes. For instance, CDK6 levels have been found to be higher in FAT1-deleted samples compared with those having wildtype FAT1 [196]. Another study has shown up-regulation of CDK4/6 and pRb levels in HER2 + breast cancer samples [334]. In ovarian cancer samples, up-regulation of CDK6 has been associated with shorted OS and immunosuppressive state [319]. Moreover, in this type of cancer, up-regulation of a functional counterpart of CDK4/6, i.e. COL6A3 has been associated with shorter OS and advanced clinical stage [330]. Table 12 shows dysregulation of CDK4/6 in clinical samples.
A number of clinical studies have evaluated the effects of CDK4/6 inhibition on survival of patients (Table 13). For instance, treatment of 22 breast cancer patients with a CDK4/6 inhibitor has resulted in complete response in one patient, partial response in 8 patients, and stable disease in 13 patients [336]. Another study in breast cancer patients has indicated better progression-free survival time in those treated with CDK4/6 inhibitors than those received PI3K inhibitors. Moreover, Combination of CDK4/6 inhibitors and endocrine therapy has yielded better OS than PI3K/mTOR inhibitors [337]. Promising results have also obtained from studies in other types of cancers.
Discussion
Expression and activity of CDKs have been assessed in animal models of cancers, cell lines and clinical samples of patients having different types of cancers. CDK1 and CDK2 are the most comprehensively assessed members of this family. Additionally, a number of studies have addressed involvement of CDKs 3, 4/6, 5, 7 and 9 in cancer cell lines. Other members of this protein family have not been thoroughly assessed.
The above-mentioned studies have revealed a number of CDKs-interacting molecules including mRNA coding genes as well as lncRNAs and miRNAs. PVT1, NCK1-AS1, FOXD2-AS1, SNHG4, SNORD52, TMPO-AS1, TONSL-AS1, DLEU1 and CASC11 are among lncRNAs that interact with CDKs. Meanwhile, miR-378a-5p, miR-34c-3p, miR-181a, miR-195-3p and miR-205 have been shown to regulate expression of certain CDKs through binding with the 3'UTR of their transcripts. Since miRNAs can efficiently reduce expression of CDKs, identification of additional CDKs-targeting miRNAs through in silico and experimental methods can facilitate design of novel treatment modalities for cancers. Moreover, available data indicate that expressions of CDKs are regulated through a complex regulatory network consisted of both genetic and epigenetic mechanisms which can be dysregulated during the course of cancer evolution. Application of various quantitative experimental and computational methods in a "system biology" approach is needed to unravel complicated aspects of the mentioned network and develop novel modalities to combat cancer-a prototype of disorders associated with dysregulation of CDKs.
Conclusion
Since activity of CDKs is associated with induction of stem cell properties, drugs targeting these proteins might be used for effective elimination of cancer stem cells and reduction of tumor metastases. This implicates that CDKs are involved in the pathogenesis of a high spectrum of cancers, including different types of carcinomas as well as non-epithelial malignancies. Coming from this point of view CDKs will come more and more in the focus as therapeutical targets.
Activity levels of CDKs can be used for prediction of cancer prognosis and response of patients to various therapeutic options. In fact, an appropriate approach for implementation of personalized medicine in the field of cancer therapy is measurement of activity of these proteins.
Cumulatively, CDKs represent ideal therapeutic targets for cancer. Thus, future studies should focus on assessment of their activities in different tumors and identification of their association with clinicopathological data. Moreover, the presence of putative genetic variants within CDK coding genes might affect their activity and susceptibility of persons to different cancers. This note should also be assessed in future studies.
Availability of data and materials
The analyzed data sets generated during the study are available from the corresponding author on reasonable request.
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Acknowledgements
The authors would like to thank the clinical Research Development Unit (CRDU) of Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran for their support, cooperation and assistance throughout the period of study.
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MT and AB designed and supervised the study. SGF and NG wrote the draft and revised it. TK, NAD, BMH and PD collected the data and designed the figures and tables. All the authors read the submitted version and approved it.
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Ghafouri-Fard, S., Khoshbakht, T., Hussen, B.M. et al. A review on the role of cyclin dependent kinases in cancers. Cancer Cell Int 22, 325 (2022). https://doi.org/10.1186/s12935-022-02747-z
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DOI: https://doi.org/10.1186/s12935-022-02747-z