RNA m⁶ A methylation regulates sorafenib resistance in liver cancer through FOXO3-mediated autophagy.

ABSTRACT: N6-methyladenosine (m⁶ A) 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 m⁶ A 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 m⁶ A modification of the FOXO3 mRNA 3'-untranslated region increasing its stability through a YTHD

SUBMITTER: Lin Z 

PROVIDER: S-EPMC7298296 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature