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

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

The EMBO journal (2020-05-06)
Ziyou Lin, Yi Niu, Arabella Wan, Dongshi Chen, Heng Liang, Xijun Chen, Lei Sun, Siyue Zhan, Liutao Chen, Chao Cheng, Xiaolei Zhang, Xianzhang Bu, Weiling He, Guohui Wan
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 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 m6 A-dependent sorafenib sensitivity. Collectively, our work reveals a critical function for METTL3-mediated m6 A modification in the hypoxic tumor microenvironment and identifies FOXO3 as an important target of m6 A modification in the resistance of HCC to sorafenib therapy.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Polybrene Infection / Transfection Reagent, A highly efficient method of gene transfer into mammalian cells leveraging infection with retroviral vectors.
Sigma-Aldrich
Calcium Phosphate Transfection Kit, Most cost effective transfection reagent kit for transient and stable transfection of DNA into mammalian cells
Sigma-Aldrich
Anti-N6-methyladenosine (m6A) Antibody, from rabbit