GSE190541 BRD4 regulates N6-methyladenosine modification of ESPL1 mRNA via interaction with RNA demethylase ALKBH5 to modulate breast cancer progression

Contributors : Hongsheng Wang ; Haisheng Zhang ; Linlin Lu ; Jiexin LiSeries Type : OtherOrganism : Homo sapiensN6-methyladenosine (m6A) is important for RNA metabolism including stability and translation of messenger RNA (mRNA). Recent studies indicate that m6A-methylated RNA can modulate dynamic chromatin accessibility and gene transcription, while the potential link of chromatin to mRNA m6A remains largely unknown. We found that targeted inhibition of bromodomain-containing protein 4 (BRD4) by siRNA or a small compound inhibitor (JQ1) significantly decreases mRNA m6A levels and suppresses the malignancy of breast cancer (BC) cells via increased expression of ALKBH5, a demethylase for mRNA methylation. Mechanistically, inhibition of BRD4 increases the mRNA stability of ALKBH5 via enhanced binding between ALKBH5 3 ’UTR with RNA-binding protein RALY. Further, BRD4 serves as a scaffold for ubiquitin enzymes TRIM21 and ALKBH5, resulting in the ubiquitination and degradation of ALKBH5 protein. JQ1-increased ALKBH5 then demethylates mRNA of ESPL1, a critical oncogenic driver for breast cancer, and reduces bindin g between ESPL1 mRNA and m6A reader IGF2BP3, leading to decay of ESPL1 mRNA. Animal and clinical studies confirm a critical role of the BRD4/ALKBH5/ESPL1 pathway in BC progression. Overall, our study sheds light on another layer of gene regulation involving crosstalks between histone modification an d RNA methylation.
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Other Homo sapiens Source Type: research