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m6A-modified circFOXK2 targets GLUT1 to accelerate oral squamous cell carcinoma aerobic glycolysis

Abstract

N6-methyladenosine (m6A) is an abundant nucleotide modification in mRNA, and its emerging roles have been gradually identified. However, the potential function of m6A and m6A-modified circular RNA (circRNA) is still unclear. Here, m6A-circRNA epitranscriptomic microarray analysis revealed a high-expressed m6A-modified circFOXK2 (hsa_circ_0000816, from FOXK2 gene) in oral squamous cell carcinoma (OSCC). For the biofunctions of OSCC, results revealed that circFOXK2 promoted the malignant phenotypes of OSCC cells. Methylated RNA immunoprecipitation sequencing (MeRIP-Seq) demonstrated that a remarkable m6A modified site was installed on glucose transporter 1 (GLUT1) mRNA. Mechanistically, circFOXK2 promoted the GLUT1 mRNA stability through cooperating with insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3) in a m6A-dependent manner. In summary, the present study explored the oncogenic role of m6A-modified circFOXK2 in OSCC through the m6A-dependent IGF2BP3/GLUT1 axis, indicating a potential therapeutic target for OSCC.

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Fig. 1: m6A-circRNA microarray analysis revealed the m6A-modified circRNA in OSCC.
Fig. 2: circFOXK2 was a m6A-modified circRNA that upregulated in OSCC.
Fig. 3: circFOXK2 accelerated the malignant phenotype of OSCC.
Fig. 4: GLUT1 acted as the target of circFOXK2.
Fig. 5: circFOXK2 cooperated with IGF2BP3 to enhance GLUT1 mRNA stability.

Data availability

The m6A-circRNA microarray data from this publication have been deposited in NCBI’s Gene Expression Omnibus database and assigned the GEO Series accession number GSE198105. The MeRIP-Seq data are available in the NCBI Gene Expression Omnibus (GEO): accession number GSE197457.

References

  1. Atashi F, Vahed N, Emamverdizadeh P, Fattahi S, Paya L. Drug resistance against 5-fluorouracil and cisplatin in the treatment of head and neck squamous cell carcinoma: a systematic review. J Dent Res Dent Clin Dent Prospects. 2021;15:219–25.

    Article  Google Scholar 

  2. Dolens EDS, Dourado MR, Almangush A, Salo TA, Gurgel Rocha CA, da Silva SD, et al. The impact of histopathological features on the prognosis of oral squamous cell carcinoma: a comprehensive review and meta-analysis. Front Oncol. 2021;11:784924.

    Article  Google Scholar 

  3. Kaminagakura E, Tango RN, Cruz-Perez D, Bonan R, Yamamoto de Almeida L, de Almeida, et al. Oral squamous cell carcinoma outcome in adolescent/young adult: systematic review and meta-analysis. Head Neck. 2022;44:548–61.

    Article  Google Scholar 

  4. Pillai J, Chincholkar T, Dixit R, Pandey M. A systematic review of proteomic biomarkers in oral squamous cell cancer. World J Surg Oncol. 2021;19:315.

    Article  Google Scholar 

  5. Russo D, Mariani P, Caponio VCA, Lo Russo L, Fiorillo L, Zhurakivska K, et al. Development and validation of prognostic models for oral squamous cell carcinoma: a systematic review and appraisal of the literature. Cancers. 2021;13:5755.

    Article  Google Scholar 

  6. Togni L, Mascitti M, Sartini D, Campagna R, Pozzi V, Salvolini E, et al. Nicotinamide N-methyltransferase in head and neck tumors: a comprehensive review. Biomolecules. 2021;11:1594.

    Article  CAS  Google Scholar 

  7. Akhtar J, Lugoboni M, Junion G. m(6)A RNA modification in transcription regulation. Transcription. 2021;12:266–76.

    Article  Google Scholar 

  8. Huang M, Xu S, Liu L, Zhang M, Guo J, Yuan Y, et al. m6A methylation regulates osteoblastic differentiation and bone remodeling. Front Cell Dev Biol. 2021;9:783322.

    Article  Google Scholar 

  9. Li H, Xiao W, He Y, Wen Z, Cheng S, Zhang Y, et al. Novel insights into the multifaceted functions of RNA n(6)-methyladenosine modification in degenerative musculoskeletal diseases. Front Cell Dev Biol. 2021;9:766020.

    Article  Google Scholar 

  10. Xu K, Dai X, Wu J, Wen K. N(6)-methyladenosine (m(6)A) reader IGF2BP2 stabilizes HK2 stability to accelerate the Warburg effect of oral squamous cell carcinoma progression. J Cancer Res Clin Oncol. 2022. https://doi.org/10.1007/s00432-022-04093-z.

  11. Zhao W, Cui Y, Liu L, Ma X, Qi X, Wang Y, 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.

    Article  CAS  Google Scholar 

  12. Fu Y, Qiu C, Yang Y, Lu J, Qi Y. CircLPAR3 acts as an oncogene in oral squamous cell carcinoma through regulating the miR-643/HMGB2 network. Biochem Genet. 2021;60:882–98.

    Article  Google Scholar 

  13. Jiang W, Zhang C, Zhang X, Sun L, Li J, Zuo J. CircRNA HIPK3 promotes the progression of oral squamous cell carcinoma through upregulation of the NUPR1/PI3K/AKT pathway by sponging miR-637. Ann Transl Med. 2021;9:860.

    Article  CAS  Google Scholar 

  14. Cui L, Huang C, Zhou D. Overexpression of circCDR1as drives oral squamous cell carcinoma progression. Oral Dis. 2021. https://doi.org/10.1111/odi.14085 Online ahead of print.

  15. Stanoeva KR, Kohl RHG, Bodewes R. Co-detection of the measles vaccine and wild-type virus by real-time PCR: public health laboratory protocol. Access Microbiol. 2021;3:000283.

    Article  Google Scholar 

  16. Anjos L, Loukissas AZ, Power DM. Proteomics of fish white muscle and western blotting to detect putative allergens. Methods Mol Biol (Clifton, N. J). 2022;2498:397–411.

    Article  Google Scholar 

  17. Fan HN, Chen ZY, Chen XY, Chen M, Yi YC, Zhu JS, et al. METTL14-mediated m(6)A modification of circORC5 suppresses gastric cancer progression by regulating miR-30c-2-3p/AKT1S1 axis. Mol Cancer. 2022;21:51.

    Article  CAS  Google Scholar 

  18. Zhao W, Cui Y, Liu L, Qi X, Liu J, Ma S, et al. Splicing factor derived circular RNA circUHRF1 accelerates oral squamous cell carcinoma tumorigenesis via feedback loop. Cell Death Differ. 2020;27:919–33.

    Article  CAS  Google Scholar 

  19. Huang X, Guo H, Wang L, Yang L, Shao Z, Zhang W. Recent advances in crosstalk between N6-methyladenosine (m6A) modification and circular RNAs in cancer. Mol Ther Nucleic Acids. 2022;27:947–55.

    Article  CAS  Google Scholar 

  20. Lu S, Ding X, Wang Y, Hu X, Sun T, Wei M, et al. The relationship between the network of non-coding RNAs-molecular targets and N6-methyladenosine modification in colorectal cancer. Front Cell Dev Biol. 2021;9:772542.

    Article  Google Scholar 

  21. Wen SY, Qadir J, Yang BB. Circular RNA translation: novel protein isoforms and clinical significance. Trends Mol Med. 2022;28:405–20.

    Article  CAS  Google Scholar 

  22. Xu T, He B, Sun H, Xiong M, Nie J, Wang S, et al. Novel insights into the interaction between N6-methyladenosine modification and circular RNA. Mol Ther Nucleic Acids. 2022;27:824–37.

    Article  CAS  Google Scholar 

  23. Wang J, Ouyang S, Zhao S, Zhang X, Cheng M, Fan X, et al. SP1-mediated upregulation of circFAM126A promotes proliferation and epithelial-mesenchymal transition of oral squamous cell carcinoma via regulation of RAB41. Front Oncol. 2022;12:715534.

    Article  Google Scholar 

  24. Fu Y, Qiu C, Yang Y, Lu J, Qi Y. CircLPAR3 acts as an oncogene in oral squamous cell carcinoma through regulating the miR-643/HMGB2 network. Biochem Genet. 2022;60:882–98.

    Article  CAS  Google Scholar 

  25. Pezzuto A, D’Ascanio M, Ricci A, Pagliuca A, Carico E. Expression and role of p16 and GLUT1 in malignant diseases and lung cancer: a review. Thorac Cancer. 2020;11:3060–70.

    Article  Google Scholar 

  26. Liu ZX, Li LM, Sun HL, Liu SM. Link between m6A modification and cancers. Front Bioeng Biotechnol. 2018;6:89.

    Article  Google Scholar 

  27. Debta P, Sarode G, Siddhartha S, Sarode S, Debta FM, Swain SK, et al. GLUT-1 expression: an aid in complementing the WHO oral epithelial dysplasia grading system. J Contemp Dent Pract. 2020;21:951–5.

    Article  Google Scholar 

  28. Angadi VC, Angadi PV. GLUT-1 immunoexpression in oral epithelial dysplasia, oral squamous cell carcinoma, and verrucous carcinoma. J Oral Sci. 2015;57:115–22.

    Article  CAS  Google Scholar 

  29. Lin C, Ma M, Zhang Y, Li L, Long F, Xie C, et al. The N(6)-methyladenosine modification of circALG1 promotes the metastasis of colorectal cancer mediated by the miR-342-5p/PGF signalling pathway. Mol Cancer. 2022;21:80.

    Article  CAS  Google Scholar 

  30. Cai J, Chen Z, Zhang Y, Wang J, Zhang Z, Wu J, et al. CircRHBDD1 augments metabolic rewiring and restricts immunotherapy efficacy via m(6)A modification in hepatocellular carcinoma. Mol Ther Oncolytics. 2022;24:755–71.

    Article  CAS  Google Scholar 

Download references

Funding

This work was supported by National Natural Science Foundation of China (No. 82002889, 82104631), Tianjin Medical University Stomatological Hospital Foundation (No: 2020YKY01), Project of integrated traditional Chinese and Western Medicine of Tianjin Health Commission (2021075), Hospital Project of Tianjin Medical University Cancer Institute and Hospital (No: B1908).

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YC, JL, and LL performed the experiments. YG and XM act as the assists. WZ and HL are responsible for the designing and funding. All authors read and approved the final manuscript.

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Correspondence to Hao Liu or Wei Zhao.

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Cui, Y., Liu, J., Liu, L. et al. m6A-modified circFOXK2 targets GLUT1 to accelerate oral squamous cell carcinoma aerobic glycolysis. Cancer Gene Ther (2022). https://doi.org/10.1038/s41417-022-00526-6

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