N6-methyladenosine modification of ITGA6 mRNA promotes the development and progression of bladder cancer

作者：Huan Jin, Xiaoling Ying, Biao Que, Xiaoxue Wang, Yinghui Chao, Haiqing Zhang, Zusen Yuan, Defeng Qi, Shuibin Lin, Min Wang, Mei Yang, Weidong Ji · 发表于：EBioMedicine · 年份：2019 · DOI：10.1016/j.ebiom.2019.07.068 · 被引用次数：205 · 研究领域：RNA modifications and cancer、Cancer-related molecular mechanisms research、Viral-associated cancers and disorders

Background Accumulating evidence has revealed the critical roles of N 6 -methyladenosine (m 6 A) modification of mRNA in various cancers. However, the biological function and regulation of m 6 A in bladder cancer (BC) are not yet fully understood. Methods We performed cell phenotype analysis and established in vivo mouse xenograft models to assess the effects of m 6 A-modified ITGA6 on BC growth and progression. Methylated RNA immunoprecipitation (MeRIP), RNA immunoprecipitation and luciferase reporter and mutagenesis assays were used to define the mechanism of m 6 A-modified ITGA6. Immunohistochemical analysis was performed to assess the correlation between METTL3 and ITGA6 expression in bladder cancer patients. Findings We show that the m 6 A writer METTL3 and eraser ALKBH5 altered cell adhesion by regulating ITGA6 expression in bladder cancer cells. Moreover, upregulation of ITGA6 is correlated with the increase in METTL3 expression in human BC tissues, and higher expression of ITGA6 in patients indicates a lower survival rate. Mechanistically, m 6 A is highly enriched within the ITGA6 transcripts, and increased m 6 A methylations of the ITGA6 mRNA 3'UTR promotes the translation of ITGA6 mRNA via binding of the m 6 A readers YTHDF1 and YTHDF3. Inhibition of ITGA6 results in decreased growth and progression of bladder cancer cells in vitro and in vivo . Furthermore, overexpression of ITGA6 in METTL3-depleted cells partially restores the BC adhesion, migration and invasion p...