METTL14-mediated N6-methyladenosine modification of Pten mRNA inhibits tumour progression in clear-cell renal cell carcinoma

Background: Clear-cell renal-cell carcinoma (ccRCC) is one of the leading causes of tumour-related death worldwide. Methyltransferase-like 14 (METTL14) is reported to regulate m6A modification in cancers. The aim of this study is to investigate the biological function and molecular mechanism of METTL14 in the pathogenesis of ccRCC.

Methods: Quantitative Real-Time PCR (qRT-PCR), western blot and immunohistochemical (IHC) assays were used to detect the expression of METTL14 and PTEN. METTL14 overexpression or knockdown was used in the in vitro and in vivo studies to investigate the biological functions of METTL14. m6A-RNA immunoprecipitation and RNA immunoprecipitation were used to investigate the m6A modification mediated by METTL14.

Results: METTL14 expression was significantly down-regulated in ccRCC tissues. Functionally, upregulation of METTL14 inhibited ccRCC cells proliferation and migration in vitro. METTL14 overexpression significantly inhibited the activation of the phosphoinositide 3 kinase (PI3K)/Akt signalling pathway. Furthermore, phosphate and tension homology deleted on chromosome ten (PTEN) is a target of METTL14. Overexpression of METTL14 increased the m6A enrichment of PTEN, and promoted PTEN expression. METTL14-enhanced PTEN mRNA stability was dependent on YTHDF1.

Conclusions: METTL14-mediated m6A modification of PTEN mRNA inhibited tumour progression, suggesting that METTL14 might be a potential prognostic biomarker and effective therapeutic target for ccRCC.