RNA m6A methylation regulates sorafenib-resistance in liver cancer through FOXO3-mediated autophagy

ABSTRACT: N6-methyladenosine (m6A) is an abundant nucleotide modification in mRNA, known to regulate mRNA stability, splicing, and translation, but it is unclear whether it is also has a physiological role in the intratumoral microenvironment and cancer drug resistance. Here, we find that METTL3, a primary m6A methyltransferase, is significantly down-regulated in human sorafenib-resistant hepatocellular carcinoma (HCC). Depletion of METTL3 under hypoxia promotes sorafenib resistance and expression of angiogenesis genes in cultured HCC cells, and activates autophagy-associated pathways. Mechanistically, we have identified FOXO3 as a key downstream target of METTL3, with m6A modification of the FOXO3 mRNA 3'-untranslated region increasing its stability through a YTHDF1-dependent mechanism. Analysis of

SUBMITTER: Ms. Ziyou Lin 

PROVIDER: S-SCDT-EMBOJ-2019-103181 | biostudies-other |

REPOSITORIES: biostudies-other