Analysis of the role of mutations in the <scp>KMT</scp>2D histone lysine methyltransferase in bladder cancer

Abstract

Histone lysine methyltransferases (HMT) comprise a subclass of epigenetic regulators; dysregulation of these enzymes affects gene expression, which may lead to tumorigenesis. Here, we performed an integrated analysis of 50 HMTs in bladder cancer and found intrinsic links between copy number alterations, mutations, gene expression levels, and clinical outcomes. Through integrative analysis, we identified six HMT genes (<i>PRDM9</i>,<i>ASH1L</i>,<i>SETD3</i>,<i>SETD5</i>,<i>WHSC1L1</i>, and <i>KMT2D</i>) that may play a key role in the development and progression of bladder cancer. Of these six HMTs, histone lysine <i>N</i>-methyltransferase 2D (<i>KMT2D</i>) exhibited the highest mutation rate in bladder cancer. Our comparison of the mRNA and miRNA expression profiles of mutated and wild-type <i>KMT2D</i> suggested that two signaling pathways (FOX1-miR-1224-5p-DLK1 and HIF/GATA5-miR-133a-3p-DRD5) may mediate the tumor suppressive effect of the <i>KMT2D</i> mutation. In summary, our findings indicate that mutations in HMT genes, especially <i>KMT2D</i> mutation, may play a role in the development of bladder cancer.