METTL3 Depletion Contributes to HR+/HER2- Breast Cancer Progression and Drug Resistance via m6A Modification of Constituents of the CDKN1A/EMT and BAX/caspase-9/-3/-8 Signalling Pathways
Research Square (Research Square)(2021)
Abstract
Abstract Background: Chemotherapy is an important strategy for the treatment of hormone receptor positive / human epidermal growth factor receptor 2 negative (HR+/HER2-) breast cancer (BC), but this subtype has a low response to chemotherapy. Growing evidence indicates that N6-methyladenosine (m6A) is the most common RNA modification in eukaryotic cells and that methyltransferase-like 3 (METTL3) participates in tumour progression in several cancer types. Therefore, exploring the function of METTL3 in HR+HER2- BC initiation and development is still significant.Methods: mRNA and protein expression levels were analysed by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting, respectively. Cell proliferation was detected by CCK-8 assays, cell migration was analysed by wound healing assays, and apoptosis was analysed by TUNEL assays. Finally, m6A modification was analysed by methylated RNA immunoprecipitation (MeRIP).Results: Chemotherapy-induced downregulation of the m6A modification is regulated by METTL3 in HR+/HER2- BC. METTL3 knockdown in MCF-7/T47D cells weakened the drug sensitivity of HR+/HER2- BC cells by promoting tumour proliferation and metastasis and inhibiting apoptosis. Mechanistically, CDKN1A was subsequently recognized as a downstream target of METTL3 that activates the AKT pathway and promotes epithelial-mesenchymal transformation (EMT). Moreover, the RNA level of BAX was decreased due to a lower level of m6A modification mediated by METTL3, and apoptosis was inhibited by inactivation of caspase 3/9/8.Conclusion: METTL3 regulates the proliferation, migration, and drug sensitivity of HR+/HER2- BC via activation of the CDKN1A/EMT and m6A-BAX/caspase 9/3/8 signalling pathways, which suggests its role as a potential biomarker for predicting the prognosis of patients with HR+/HER2- BC.
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Key words
breast cancer
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