RNA m ⁶ A methylation regulates sorafenib resistance in liver cancer through FOXO 3‐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 clinical samples furthermore showed that METTL3 and FOXO3 levels are tightly correlated in HCC patients. In mouse xenograft models, METTL3 depletion significantly enhances sorafenib resistance of HCC by abolishing the identified METTL3‐mediated FOXO3 mRNA stabilization, and overexpression of FOXO3 restores m6A‐dependent sorafenib sensitivity. Collectively, our work reveals a critical function for METTL3‐mediated m6A modification in the hypoxic tumor microenvironment and identifies FOXO3 as an important target of m6A modification in the resistance of HCC to sorafenib therapy.

RNA-binding protein RALY reprogrammes mitochondrial metabolism via mediating miRNA processing in colorectal cancer

“…Recently, N6-methyladenosine modification has been shown as critical post-transcriptional regulation for gene expression in tumour development, and plays important roles in RNA splicing and degradation. [49][50][51][52] Previous studies reported that hnRNP proteins promoted some miRNAs processing by recognising the m 6 A-modified pri-miRNAs transcripts. [32][33][34] As a member of the hnRNPC subfamily, RALY is now found to recognise the terminal loop region of pri-miR-877 with m 6 A modification, and facilitate the binding of pri-miR-877 to the microprocessor complex, thus promoting its processing.…”

MiR-375 gene therapy attenuates drug resistance of hepatocellular carcinoma cells by inhibiting cell autophagy

“…For instance, SNHG16 promoted sorafenib resistance by enhancing autophagy via the miR-23b-3p/ EGR1 axis in HCC [19]. The METTL3/FOXO3 axis regulated autophagyinduced sorafenib resistance in HCC through the methylation of N6-methyladenosine [20]. The LC3II/LC3I ratio was increased and p62 was decreased in HepG2/so cells in comparison with HepG2 cells, suggesting activated autophagy in sorafenib-resistant HCC cells.…”

The mechanism of m6A methyltransferase METTL3-mediated autophagy in reversing gefitinib resistance in NSCLC cells by β-elemene

“…Besides m 6 A methyltransferases, whether there are any other m 6 A modulators (m 6 A demethylase and binding proteins) involved in this autophagy flux regulation is still unknown, which needs further study to explore. Increasing number of evidence shows that m 6 A plays a key role in regulating autophagy 33,34 . For instance, FTO regulates autophagy through targeting ATG5 and ATG7.…”