Loss of tumor suppressor KDM6A amplifies PRC2-regulated transcriptional repression in bladder cancer and can be targeted through inhibition of EZH2

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.

Authors: Lian Dee Ler,1,2,3 Sujoy Ghosh,4,5 Xiaoran Chai,5 Aye Aye Thike,6 Hong Lee Heng,1,2 Ee Yan Siew,1,2 Sucharita Dey,7 Liang Kai Koh,1,2 Jing Quan Lim,1,2 Weng Khong Lim,1,2 Swe Swe Myint,1,2 Jia Liang Loh,1,2 Pauline Ong,1,2 Xin Xiu Sam,6 Dachuan Huang,1,2 Tony Lim,6 Puay Hoon Tan,6 Sanjanaa Nagarajan,1,2 Christopher Wai Sam Cheng,8 Henry Ho,8 Lay Guat Ng,8 John Yuen,8 Po-Hung Lin,9 Cheng-Keng Chuang,9 Ying-Hsu Chang,9 Wen-Hui Weng,10 Steven G. Rozen,2,5 Patrick Tan,2,7,11,12 Caretha L. Creasy,13 See-Tong Pang,9* Michael T. McCabe,13* Song Ling Poon,1,2* Bin Tean Teh1,2,7,14*

Author Affiliations: 1Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, 11HospitalDrive, Singapore 169610, Singapore. 2Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore. 3NUS Graduate School for Integrative Sciences and Engineering, 28Medical Drive, Singapore 117456, Singapore. 4Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore 169857, Singapore. 5Centre for Computational Biology, Duke-NUS Medical School, Singapore 169857, Singapore. 6Department of Pathology, Singapore General Hospital, Singapore, Singapore. 7Cancer Science Institute of Singapore, National University of Singapore, Centre for Life Sciences, Singapore 117456, Singapore. 8Department of Urology, Singapore General Hospital, Outram Road, Singapore 169608, Singapore. 9Division of Urooncology, Department of Urology, Chang Gung University and Memorial Hospital at LinKou, TaoYuan, Taiwan. 10Department of Chemical Engineering and Biotechnology and Graduate Institute of Biochemical and Biomedical Engineering, National Taipei University of Technology, Taipei, Taiwan. 11Division of Cellular and Molecular Research, National Cancer Centre
Singapore, Singapore 169610, Singapore. 12Genome Institute of Singapore, 60 Biopolis Street Genome, Singapore 138672, Singapore. 13Cancer Epigenetics Discovery Performance Unit, Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA. 14Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, #07-18, Singapore 138673, Singapore.

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