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Sci Transl Med. 2017 Feb 22;9(378). pii: eaai8312. doi: 10.1126/scitranslmed.aai8312.

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

Ler LD1,2,3, Ghosh S4,5, Chai X5, Thike AA6, Heng HL1,2, Siew EY1,2, Dey S7, Koh LK1,2, Lim JQ1,2, Lim WK1,2, Myint SS1,2, Loh JL1,2, Ong P1,2, Sam XX6, Huang D1,2, Lim T6, Tan PH6, Nagarajan S1,2, Cheng CW8, Ho H8, Ng LG8, Yuen J8, Lin PH9, Chuang CK9, Chang YH9, Weng WH10, Rozen SG2,5, Tan P2,7,11,12, Creasy CL13, Pang ST14, McCabe MT15, Poon SL16,2, Teh BT16,2,7,17.

Author information

1
Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, 11 Hospital Drive, Singapore 169610, Singapore.
2
Program in Cancer and Stem Cell Biology, Duke-NUS Medical School, 8 College Road, Singapore 169857, Singapore.
3
NUS Graduate School for Integrative Sciences and Engineering, 28 Medical Drive, Singapore 117456, Singapore.
4
Program in Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, Singapore 169857, Singapore.
5
Centre for Computational Biology, Duke-NUS Medical School, Singapore 169857, Singapore.
6
Department of Pathology, Singapore General Hospital, Singapore, Singapore.
7
Cancer Science Institute of Singapore, National University of Singapore, Centre for Life Sciences, Singapore 117456, Singapore.
8
Department of Urology, Singapore General Hospital, Outram Road, Singapore 169608, Singapore.
9
Division of Urooncology, Department of Urology, Chang Gung University and Memorial Hospital at LinKou, TaoYuan, Taiwan.
10
Department of Chemical Engineering and Biotechnology and Graduate Institute of Biochemical and Biomedical Engineering, National Taipei University of Technology, Taipei, Taiwan.
11
Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore 169610, Singapore.
12
Genome Institute of Singapore, 60 Biopolis Street Genome, Singapore 138672, Singapore.
13
Cancer Epigenetics Discovery Performance Unit, Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA.
14
Division of Urooncology, Department of Urology, Chang Gung University and Memorial Hospital at LinKou, TaoYuan, Taiwan. teh.bin.tean@singhealth.com.sg songling.poon@gmail.com michael.t.mccabe@gsk.com jacobpang@adm.cgmh.org.tw.
15
Cancer Epigenetics Discovery Performance Unit, Oncology R&D, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA. teh.bin.tean@singhealth.com.sg songling.poon@gmail.com michael.t.mccabe@gsk.com jacobpang@adm.cgmh.org.tw.
16
Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, 11 Hospital Drive, Singapore 169610, Singapore. teh.bin.tean@singhealth.com.sg songling.poon@gmail.com michael.t.mccabe@gsk.com jacobpang@adm.cgmh.org.tw.
17
Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, #07-18, Singapore 138673, Singapore.

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.

PMID:
28228601
DOI:
10.1126/scitranslmed.aai8312
[Indexed for MEDLINE]

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