?-catenin represses miR455-3p to stimulate m6A modification of HSF1 mRNA and promote its translation in colorectal cancer.

ABSTRACT: BACKGROUND:Heat shock transcription factor1 (HSF1) was overexpressed to promote glutaminolysis and activate mTOR in colorectal cancer (CRC). Here, we investigated the mechanism for cancer-specific overexpression of HSF1. METHODS:HSF1 expression was analyzed by chromatin immunoprecipitation, qRT-PCR, immunohistochemistry staining and immunoblotting. HSF1 translation was explored by polysome profiling and nascent protein analysis. Biotin pulldown and m6A RNA immunoprecipitation were applied to investigate RNA/RNA interaction and m6A modification. The relevance of HSF1 to CRC was analyzed in APCmin/+ and APCmin/+ HSF1+/-mice. RESULTS:HSF1 expression and activity were reduced after the inhibition of WNT/?-catenin signaling by pyrvinium or ?-catenin knockdown, but elevated upon its activation by lithium chloride (LiCl) or ?-catenin overexpression. There are much less upregulated genes in HSF1-KO MEF treated with LiCl when compared with LiCl-treated WT MEF. HSF1 protein expression was positively correlated with ?-catenin expression in cell lines and primary tissues. After ?-catenin depletion, HSF1 mRNA translation was impaired, accompanied by the reduction of its m6A modification and the upregulation of miR455-3p, which can interact with 3'-UTR of HSF1 mRNA to repress its translation. Interestingly, inhibition of miR455-3p rescued ?-catenin depletion-induced reduction of HSF1 m6A modification and METTL3 interaction. Both the size and number of tumors were significantly reduced in APCmin/+ mice when HSF1 was genetically knocked-out or chemically inhibited. CONCLUSIONS:?-catenin suppresses miR455-3p generation to stimulate m6A modification and subsequent translation of HSF1 mRNA. HSF1 is important for ?-catenin to promote CRC development. Targeting HSF1 could be a potential strategy for the intervention of ?-catenin-driven cancers.

SUBMITTER: Song P 

PROVIDER: S-EPMC7446108 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature