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KDM6A loss creates a new therapeutic targeting opportunity in bladder cancers - Beyond the Abstract

Recent genomic analysis of muscle-invasive bladder cancers identified mutations in chromatin remodeling genes such as KDM6A. This gene is a demethylase that removes of methyl groups from H3K27me3 resulting in opening chromatin to transcription. Until recently, the precise role of this gene in bladder cancer was poorly understood.
A new study published in the journal Science Translational Medicine is very illuminating in this respect. The authors identified that KDM6A is mutated at a rate of 36% in non-muscle-invasive and 24% of muscle-invasive bladder cancer. Having established that KDM6A mutations are highly prevalent in bladder cancers, the investigators then proceeded to define the functional role of KDM6A loss. They created a KDM6A knockout clones in RT-4, a wild-type KDM6A bladder carcinoma cell line and observed that KDM6A inactivation results in faster proliferation of these cancer cells.

One of the most important findings was that KDM6A loss resulted in a dependency on EZH2, a potential therapeutic target. Pharmacologic EZH2 inhibition resulted in decreased growth KDM6A-null patient-derived and cell line xenografts.

This study reveals significant insights into the oncogenic results of KDM6A loss in bladder cancer and identifies a novel targeted therapeutic strategy for KDM6A-mutant bladder tumors.

Read the Abstract

Author: Bishoy M. Faltas MD

Reference:

By Lian Dee Ler, Sujoy Ghosh, Xiaoran Chai, Aye Aye Thike, Hong Lee Heng, Ee Yan Siew, Sucharita Dey, Liang Kai Koh, Jing Quan Lim, Weng Khong Lim, Swe Swe Myint, Jia Liang Loh, Pauline Ong, Xin Xiu Sam, Dachuan Huang, Tony Lim, Puay Hoon Tan, Sanjanaa Nagarajan, Christopher Wai Sam Cheng, Henry Ho, Lay Guat Ng, John Yuen, Po-Hung Lin, Cheng-Keng Chuang, Ying-Hsu Chang, Wen-Hui Weng, Steven G. Rozen, Patrick Tan, Caretha L. Creasy, See-Tong Pang, Michael T. McCabe, Song Ling Poon, Bin Tean The. Loss of tumor suppressor KDM6A amplifies PRC2-regulated transcriptional repression in bladder cancer and can be targeted through inhibition of EZH2. Science Translational Medicine22 Feb 2017