1. Loss of tumor suppressor KDM6A amplifies PRC2-regulated transcriptional repression in bladder cancer and can be targeted through inhibition of EZH2.
- Author
-
Ler LD, Ghosh S, Chai X, Thike AA, Heng HL, Siew EY, Dey S, Koh LK, Lim JQ, Lim WK, Myint SS, Loh JL, Ong P, Sam XX, Huang D, Lim T, Tan PH, Nagarajan S, Cheng CW, Ho H, Ng LG, Yuen J, Lin PH, Chuang CK, Chang YH, Weng WH, Rozen SG, Tan P, Creasy CL, Pang ST, McCabe MT, Poon SL, and Teh BT
- Subjects
- Animals, Cell Line, Tumor, Cell Proliferation genetics, Enhancer of Zeste Homolog 2 Protein metabolism, Gene Expression Regulation, Neoplastic, Insulin-Like Growth Factor Binding Protein 3 metabolism, Mice, Nude, Models, Biological, Neoplasm Invasiveness, Urinary Bladder Neoplasms pathology, Urothelium pathology, Enhancer of Zeste Homolog 2 Protein antagonists & inhibitors, Histone Demethylases metabolism, Nuclear Proteins metabolism, Polycomb Repressive Complex 2 metabolism, Transcription, Genetic, Urinary Bladder Neoplasms genetics
- Abstract
Trithorax-like group complex containing KDM6A acts antagonistically to Polycomb-repressive complex 2 (PRC2) containing EZH2 in maintaining the dynamics of the repression and activation of gene expression through H3K27 methylation. In urothelial bladder carcinoma, KDM6A (a H3K27 demethylase) is frequently mutated, but its functional consequences and therapeutic targetability remain unknown. About 70% of KDM6A mutations resulted in a total loss of expression and a consequent loss of demethylase function in this cancer type. Further transcriptome analysis found multiple deregulated pathways, especially PRC2/EZH2, in KDM6A -mutated urothelial bladder carcinoma. Chromatin immunoprecipitation sequencing analysis revealed enrichment of H3K27me3 at specific loci in KDM6A -null cells, including PRC2/EZH2 and their downstream targets. Consequently, we targeted EZH2 (an H3K27 methylase) and demonstrated that KDM6A -null urothelial bladder carcinoma cell lines were sensitive to EZH2 inhibition. Loss- and gain-of-function assays confirmed that cells with loss of KDM6A are vulnerable to EZH2. IGFBP3, a direct KDM6A/EZH2/H3K27me3 target, was up-regulated by EZH2 inhibition and contributed to the observed EZH2-dependent growth suppression in KDM6A -null cell lines. EZH2 inhibition delayed tumor onset in KDM6A -null cells and caused regression of KDM6A -null bladder tumors in both patient-derived and cell line xenograft models. In summary, our study demonstrates that inactivating mutations of KDM6A , which are common in urothelial bladder carcinoma, are potentially targetable by inhibiting EZH2., (Copyright © 2017, American Association for the Advancement of Science.)
- Published
- 2017
- Full Text
- View/download PDF