Skip to main content

Advertisement

SpringerLink
Log in

ALKBH5 facilitates the progression of infantile hemangioma by increasing FOXF1 expression in a m6A-YTHDF2 dependent manner to activate HK-2 signaling

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

Alkylation repair homolog protein 5 (ALKBH5) is reported to participate in infantile hemangioma (IH) progression. However, the underlying mechanism of ALKBH5 in IH remains unclear. Using qRT-PCR and Western blotting, ALKBH5, forkhead box F1 (FOXF1) and hexokinase 2 (HK-2) expressions in IH tissues and IH-derived endothelial cells XPTS-1 were assessed. The Me-RIP assay was used to analyze FOXF1 m6A level. CCK8, colony formation, flow cytometry and transwell assays were employed to determine IH cell viability, proliferation, apoptosis, migration and invasion. The interactions between YTH (YT521-B homology) domain 2 (YTHDF2), FOXF1 and HK-2 were analyzed by RIP, dual luciferase reporter gene assay and/or ChIP assay. The in vivo IH growth was evaluated in immunocompromised mice. FOXF1 was overexpressed in IH tissues, and its silencing inhibited IH cell proliferation, migration and invasion whereas promoting cell apoptosis in vitro. ALKBH5 upregulation facilitated FOXF1 mRNA stability and expression in IH cells in a m6A-YTHDF2-dependent manner. FOXF1 downregulation reversed the impact of ALKBH5 upregulation on IH cellular phenotypes. It also turned out that FOXF1 positively regulated HK-2 expression in IH cells through interacting with the HK-2 promoter. HK-2 upregulation abolished FOXF1 knockdown’s inhibition on IH cell aggressive behaviors. ALKBH5 or FOXF1 silencing suppressed IH tumor development via HK-2 signaling in immunocompromised mice. ALKBH5 promoted FOXF1 expression m6A-YTHDF2 dependently, which in turn elevated HK-2 expression, thereby accelerating IH development.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data availability

All data generated or analyzed during this study are included in this article. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

IH:

Infantile hemangioma

HK-2:

Hexokinase 2

FOXF1:

Forkhead box F1

ALKBH5:

Alkylation repair homolog protein 5

m6A:

N6-Methyladenosine

IHC:

Immunohistochemistry

qRT-PCR:

Quantitative real-time polymerase chain reaction

SDS-PAGE:

Sodium dodecyl sulfate–polyacrylamide gel electrophoresis

Me-RIP:

Methylated RNA binding protein immunoprecipitation

SD:

Standard deviation

ANOVA:

Analysis of variance

DMEM:

Dulbecco's modified eagle media

References

  1. Solman L, Glover M, Beattie PE, Buckley H, Clark S, Gach JE et al (2018) Oral propranolol in the treatment of proliferating infantile haemangiomas: British society for paediatric dermatology consensus guidelines. Br J Dermatol 179:582–589

    Article  CAS  PubMed  Google Scholar 

  2. Liu C, Zhao Z, Ji Z, Jiang Y, Zheng J (2019) Mir-187-3p enhances propranolol sensitivity of hemangioma stem cells. Cell Struct Funct 44:41–50

    Article  CAS  PubMed  Google Scholar 

  3. Satterfield KR, Chambers CB (2019) Current treatment and management of infantile hemangiomas. Surv Ophthalmol 64:608–618

    Article  PubMed  Google Scholar 

  4. Pan Y, Ma P, Liu Y, Li W, Shu Y (2018) Multiple functions of m(6)a rna methylation in cancer. J Hematol Oncol 11:48

    Article  PubMed  PubMed Central  Google Scholar 

  5. Zhao H, Xu Y, Xie Y, Zhang L, Gao M, Li S et al (2021) M6a regulators is differently expressed and correlated with immune response of esophageal cancer. Front Cell Dev Biol 9:650023

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  6. Guo T, Liu DF, Peng SH, Xu AM (2020) Alkbh5 promotes colon cancer progression by decreasing methylation of the lncrna neat1. Am J Transl Res 12:4542–4549

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Shen G, Ren H, Shang Q, Zhao W, Zhang Z, Yu X et al (2020) Foxf1 knockdown promotes bmsc osteogenesis in part by activating the wnt/β-catenin signalling pathway and prevents ovariectomy-induced bone loss. EBioMedicine 52:102626

    Article  PubMed  PubMed Central  Google Scholar 

  8. Wang S, Yan S, Zhu S, Zhao Y, Yan J, Xiao Z et al (2018) Foxf1 induces epithelial-mesenchymal transition in colorectal cancer metastasis by transcriptionally activating snai1. Neoplasia 20:996–1007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Zhang Y, Wang P (2022) Foxf1 was identified as a novel biomarker of infantile hemangioma by weighted coexpression network analysis and differential gene expression analysis. Contrast Media Mol Imaging 2022:8981078

    PubMed  PubMed Central  Google Scholar 

  10. Zhang Y, Ren YJ, Guo LC, Ji C, Hu J, Zhang HH et al (2017) Nucleus accumbens-associated protein-1 promotes glycolysis and survival of hypoxic tumor cells via the hdac4-hif-1α axis. Oncogene 36:4171–4181

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ganapathy-Kanniappan S, Geschwind JF (2013) Tumor glycolysis as a target for cancer therapy: progress and prospects. Mol Cancer 12:152

    Article  PubMed  PubMed Central  Google Scholar 

  12. Yang K, Qiu T, Zhou J, Gong X, Zhang X, Lan Y et al (2023) Blockage of glycolysis by targeting pfkfb3 suppresses the development of infantile hemangioma. J Transl Med 21:85

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ciscato F, Ferrone L, Masgras I, Laquatra C, Rasola A (2021) Hexokinase 2 in cancer: A prima donna playing multiple characters. Int J Mol Sci 22:8

    Article  Google Scholar 

  14. Chen J, Wu D, Dong Z, Chen A, Liu S (2020) The expression and role of glycolysis-associated molecules in infantile hemangioma. Life Sci 259:118215

    Article  CAS  PubMed  Google Scholar 

  15. Wang J, Shao F, Yang Y, Wang W, Yang X, Li R et al (2022) A non-metabolic function of hexokinase 2 in small cell lung cancer: Promotes cancer cell stemness by increasing usp11-mediated cd133 stability. Cancer Commun (Lond, Engl) 42:1008–1027

    Article  Google Scholar 

  16. Fu Y, Dominissini D, Rechavi G, He C (2014) Gene expression regulation mediated through reversible m6a rna methylation. Nat Rev Genet 15:293–306

    Article  CAS  PubMed  Google Scholar 

  17. Cheng M, Sheng L, Gao Q, Xiong Q, Zhang H, Wu M et al (2019) The m(6)a methyltransferase mettl3 promotes bladder cancer progression via aff4/nf-κb/myc signaling network. Oncogene 38:3667–3680

    Article  CAS  PubMed  Google Scholar 

  18. Ensfelder TT, Kurz MQ, Iwan K, Geiger S, Matheisl S, Müller M et al (2018) Alkbh5-induced demethylation of mono- and dimethylated adenosine. Chem Commun (Camb) 54:8591–8593

    Article  CAS  PubMed  Google Scholar 

  19. Zhang J, Guo S, Piao HY, Wang Y, Wu Y, Meng XY et al (2019) Alkbh5 promotes invasion and metastasis of gastric cancer by decreasing methylation of the lncrna neat1. J Physiol Biochem 75:379–389

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chao Y, Shang J, Ji W (2020) Alkbh5-m(6)a-foxm1 signaling axis promotes proliferation and invasion of lung adenocarcinoma cells under intermittent hypoxia. Biochem Biophys Res Commun 521:499–506

    Article  CAS  PubMed  Google Scholar 

  21. Wu CY, Chan CH, Dubey NK, Wei HJ, Lu JH, Chang CC et al (2020) Highly expressed foxf1 inhibit non-small-cell lung cancer growth via inducing tumor suppressor and g1-phase cell-cycle arrest. Int J Mol Sci 21:89

    Article  Google Scholar 

  22. Wendling DS, Lück C, von Schweinitz D, Kappler R (2008) Characteristic overexpression of the forkhead box transcription factor foxf1 in patched-associated tumors. Int J Mol Med 22:787–792

    CAS  PubMed  Google Scholar 

  23. Laé M, Ahn EH, Mercado GE, Chuai S, Edgar M, Pawel BR et al (2007) Global gene expression profiling of pax-fkhr fusion-positive alveolar and pax-fkhr fusion-negative embryonal rhabdomyosarcomas. J Pathol 212:143–151

    Article  PubMed  Google Scholar 

  24. Lo PK, Lee JS, Chen H, Reisman D, Berger FG, Sukumar S (2013) Cytoplasmic mislocalization of overexpressed foxf1 is associated with the malignancy and metastasis of colorectal adenocarcinomas. Exp Mol Pathol 94:262–269

    Article  CAS  PubMed  Google Scholar 

  25. Yang Z, Cai Z, Yang C, Luo Z, Bao X (2022) Alkbh5 regulates stat3 activity to affect the proliferation and tumorigenicity of osteosarcoma via an m6a-ythdf2-dependent manner. EBioMedicine 80:104019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Guo X, Li K, Jiang W, Hu Y, Xiao W, Huang Y et al (2020) Rna demethylase alkbh5 prevents pancreatic cancer progression by posttranscriptional activation of per1 in an m6a-ythdf2-dependent manner. Mol Cancer 19:91

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. DeWaal D, Nogueira V, Terry AR, Patra KC, Jeon SM, Guzman G et al (2018) Hexokinase-2 depletion inhibits glycolysis and induces oxidative phosphorylation in hepatocellular carcinoma and sensitizes to metformin. Nat Commun 9:446

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  28. Mathupala SP, Ko YH, Pedersen PL (2006) Hexokinase ii: Cancer’s double-edged sword acting as both facilitator and gatekeeper of malignancy when bound to mitochondria. Oncogene 25:4777–4786

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Yang L, Yan X, Chen J, Zhan Q, Hua Y, Xu S et al (2021) Hexokinase 2 discerns a novel circulating tumor cell population associated with poor prognosis in lung cancer patients. Proc Nat Acad Sci USA 118:89

    Google Scholar 

  30. Li P, Xiao XE, Xu Q, Guo ZT (2011) establishment of human infancy hemangioma-derived endothelial cell line xpts-1 and animal model of human infancy hemangioma. Chin J Stomatol 46:129–133

    Google Scholar 

  31. Wu ZB, Shi SL, Pan FJ, Li L, Chen HY (2021) Propranolol inhibits infantile hemangioma by regulating the mir-424/vascular endothelial growth factor-a (vegfa) axis. Transl Pediatr 10:1867–1876

    Article  PubMed  PubMed Central  Google Scholar 

  32. Li D, Li P, Guo Z, Wang H, Pan W (2017) Downregulation of mir-382 by propranolol inhibits the progression of infantile hemangioma via the pten-mediated akt/mtor pathway. Int J Mol Med 39:757–763

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by Scientific Research Project of Hunan Provincial Health Commission (No.202206023142).

Author information

Authors and Affiliations

  1. Department of Fetal and Neonatal Surgery, Hunan Children’s Hospital, No.86, Ziyuan Road, Yuhua District, Changsha, 410007, Hunan, People’s Republic of China

    Kun Peng, Ren-Peng Xia, Fan Zhao, Yong Xiao, Ti-Dong Ma, Ming Li, Yong Feng & Chong-Gao Zhou

Authors
  1. Kun Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ren-Peng Xia
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fan Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yong Xiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ti-Dong Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ming Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yong Feng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chong-Gao Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

KP: Conceptualization; Writing-original draft; Methodology; Formal analysis; RPX: Supervision; Validation; FZ: Data curation; YX: Resources; TDM: Investigation; ML: Software; YF: Visualization; CGZ: Project administration; Funding acquisition; Writing-review & editing. KP, RPX, FZ, YX, TDM, ML, YF, CGZ have read and approved the final version of this manuscript to be published.

Corresponding author

Correspondence to Chong-Gao Zhou.

Ethics declarations

Conflict of interest

The authors declare that there is no conflict of interest.

Consent for publication

The informed consent was obtained from study participants.

Ethical approval

This study was passed after review of Ethics Committee of Hunan children's Hospital before enrollment of patients and all participants signed informed consent. The animal studies were approved by the Ethics Committee of Hunan children's Hospital.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

11010_2024_4936_MOESM1_ESM.tif

The mRNA level of HK-2, GLUT1, PKM2 and LDHA in XPTS-1 cells after shNC or shFOXF1 transfection was detected by qRT-PCR. The data were expressed as mean ± SD. All data was obtained from at least three replicate experiments. *p < 0.05, **p < 0.01. Two group differences was determined using Student’s t test. Supplementary file1 (TIF 934 kb)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Peng, K., Xia, RP., Zhao, F. et al. ALKBH5 facilitates the progression of infantile hemangioma by increasing FOXF1 expression in a m6A-YTHDF2 dependent manner to activate HK-2 signaling. Mol Cell Biochem (2024). https://doi.org/10.1007/s11010-024-04936-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11010-024-04936-y

Keywords

Search

Navigation