N-6-Methyladenosine Methyltransferase METTL16 Suppresses the Proliferation of Pancreatic Adenocarcinoma Cancer Through P21 Pathways

INTRODUCTION: Many studies have reported that N6-methyladenosine (m6A) modification plays a critical role in the epigenetic regulation of organisms, especially in the pathogenesis of malignant disease. However, m6A research mainly focused on the methyltransferase mediated by METTL3, but few by METTL16. The aim of this study is to investigate the mechanism of METTL16 which mediated m6A modification and its role in pancreatic adenocarcinoma cancer (PDAC) proliferation. METHODS: Clinicopathologic and survival data were retrospectively collected from 175 PDAC patients from multiple clinical centers. The METTL16, CCK8 expression, cell cycle assay, EdU assay, and xenograft mouse model were used to evaluate the proliferation effect of METTL16. Potential downstream pathways and the mechanisms were explored via RNA sequencing, m6A sequencing, and bioinformatic analyses. The regulatory mechanism was studied through methyltransferase inhibition assay, reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), and Western blotting. RESULTS: We found that METTL16 expression was markedly downregulated in PDAC and multivariate Cox regression analyses revealed that METTL16 was a protective factor for PDAC patients. We also demonstrated that METTL16 overexpression inhibited the PDAC cell proliferation. We identified a METTL16-p21 signaling axis, in which the downregulation of METTL16 resulted in the inhibition of p21. In addition, METTL16 silencing and overexpression highlighted the alterations in m6A modification in PDAC (Figure).FigureCONCLUSION: We concluded that METTL16 played a tumor-suppressive role in the proliferation of PDAC through the p21 pathway by mediating m6A modification. METTL16 may be a novel marker and target for the carcinogenesis and treatment of PDAC.