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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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.
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.
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.
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.
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.
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.
Akhtar J, Lugoboni M, Junion G. m(6)A RNA modification in transcription regulation. Transcription. 2021;12:266–76.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Wen SY, Qadir J, Yang BB. Circular RNA translation: novel protein isoforms and clinical significance. Trends Mol Med. 2022;28:405–20.
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.
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.
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.
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.
Liu ZX, Li LM, Sun HL, Liu SM. Link between m6A modification and cancers. Front Bioeng Biotechnol. 2018;6:89.
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.
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.
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.
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.
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).
The authors declare no competing interests.
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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 30, 163–171 (2023). https://doi.org/10.1038/s41417-022-00526-6