METTL3 facilitates prostate cancer progression via inducing HOXC6 m6A modification and stabilizing its expression through IGF2BP2-dependent mechanisms

• Published in: Molecular and cellular biochemistry 2024-07, Vol.479 (7), p.1707-1720
• Main Authors: He, Peng, Liu, Xuehui, Yu, Gui, Wang, Yu, Wang, Shize, Liu, Jing, An, Yu
• Format: Article
• Language: English
• Subjects: Adenosine diphosphate; Assaying; Biochemistry; Biomedical and Life Sciences; Cancer Research; Cardiology; Cell growth; Cell migration; Cell proliferation; Cholecystokinin; Flow cytometry; Gene expression; Glycolysis; Homeobox; Immunoprecipitation; In vivo methods and tests; Kinases; Life Sciences; Medical Biochemistry; Methyltransferase; mRNA stability; N6-methyladenosine; Phosphoglycerate kinase; Phosphoglycerate kinase 1; Prostate cancer; RNA modification
• ISSN: 0300-8177; 1573-4919; 1573-4919
• DOI: 10.1007/s11010-024-05023-y

HOXC6 (Homeobox C6) and methyltransferase-like 3 (METTL3) have been shown to be involved in the progression of prostate cancer (PCa). However, whether HOXC6 performs oncogenic effects in PCa via METTL3-mediated N6-methyladenosine (m6A) modification is not yet reported. The Cell Counting Kit-8 (CCK-8), 5-ethynyl-2′-deoxyuridine (EdU), flow cytometry, transwell, scratch, sphere formation assays were applied for cell growth, invasion, migration and stemness analyses. Glycolysis was evaluated by measuring glucose consumption, lactate generation and ATP/ADP ratio. The N6-methyladenine (m6A) modification profile was determined by RNA immunoprecipitation (Me-RIP) assay. The proteins that interact with PGK1 (phosphoglycerate kinase 1) were confirmed by Co-immunoprecipitation assay. Tumor formation experiments in mice were conducted for in vivo assay. PCa tissues and cells showed highly expressed HOXC6 and METTL3. Functionally, the silencing of HOXC6 or METTL3 suppresses PCa cell proliferation, invasion, migration, stemness, and glycolysis. Moreover, METTL3-induced HOXC6 m6A modification to stabilize its expression. In addition, the m6A reader IGF2BP2 directly recognized and bound to HOXC6 mRNA, and maintained its stability, and was involved in the regulation of HOXC6 expression by METTL3. Furthermore, IGF2BP2 knockdown impaired PCa cell proliferation, invasion, migration, stemness, and glycolysis by regulating HOXC6. Besides that HOXC6 interacted with the glycoytic enzyme PGK1 in PCa cells. In vivo assays further showed that METTL3 silencing reduced the expression of HOXC6 and PGK1, and impeded PCa growth . METTL3 promoted PCa progression by maintaining HOXC6 expression in an m6A-IGF2BP2-dependent mechanism.