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

      1 , 2 , 3 , 4 , 5 , 5 , 6 , 1 , 2 , 1 , 2 , 7 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 1 , 2 , 6 , 1 , 2 , 6 , 6 , 1 , 2 , 8 , 8 , 8 , 8 , 9 , 9 , 9 , 10 , 2 , 5 , 2 , 7 , 11 , 12 , 13 , 14 , 15 , 16 , 2 , 16 , 2 , 7 , 17
      Science translational medicine
      American Association for the Advancement of Science (AAAS)

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          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.

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          Most cited references39

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          MMPBSA.py: An Efficient Program for End-State Free Energy Calculations.

          MM-PBSA is a post-processing end-state method to calculate free energies of molecules in solution. MMPBSA.py is a program written in Python for streamlining end-state free energy calculations using ensembles derived from molecular dynamics (MD) or Monte Carlo (MC) simulations. Several implicit solvation models are available with MMPBSA.py, including the Poisson-Boltzmann Model, the Generalized Born Model, and the Reference Interaction Site Model. Vibrational frequencies may be calculated using normal mode or quasi-harmonic analysis to approximate the solute entropy. Specific interactions can also be dissected using free energy decomposition or alanine scanning. A parallel implementation significantly speeds up the calculation by dividing frames evenly across available processors. MMPBSA.py is an efficient, user-friendly program with the flexibility to accommodate the needs of users performing end-state free energy calculations. The source code can be downloaded at http://ambermd.org/ with AmberTools, released under the GNU General Public License.
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            UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development.

            The trithorax and the polycomb group proteins are chromatin modifiers, which play a key role in the epigenetic regulation of development, differentiation and maintenance of cell fates. The polycomb repressive complex 2 (PRC2) mediates transcriptional repression by catalysing the di- and tri-methylation of Lys 27 on histone H3 (H3K27me2/me3). Owing to the essential role of the PRC2 complex in repressing a large number of genes involved in somatic processes, the H3K27me3 mark is associated with the unique epigenetic state of stem cells. The rapid decrease of the H3K27me3 mark during specific stages of embryogenesis and stem-cell differentiation indicates that histone demethylases specific for H3K27me3 may exist. Here we show that the human JmjC-domain-containing proteins UTX and JMJD3 demethylate tri-methylated Lys 27 on histone H3. Furthermore, we demonstrate that ectopic expression of JMJD3 leads to a strong decrease of H3K27me3 levels and causes delocalization of polycomb proteins in vivo. Consistent with the strong decrease in H3K27me3 levels associated with HOX genes during differentiation, we show that UTX directly binds to the HOXB1 locus and is required for its activation. Finally mutation of F18E9.5, a Caenorhabditis elegans JMJD3 orthologue, or inhibition of its expression, results in abnormal gonad development. Taken together, these results suggest that H3K27me3 demethylation regulated by UTX/JMJD3 proteins is essential for proper development. Moreover, the recent demonstration that UTX associates with the H3K4me3 histone methyltransferase MLL2 (ref. 8) supports a model in which the coordinated removal of repressive marks, polycomb group displacement, and deposition of activating marks are important for the stringent regulation of transcription during cellular differentiation.
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              Polycomb silencers control cell fate, development and cancer.

              Polycomb group (PcG) proteins are epigenetic gene silencers that are implicated in neoplastic development. Their oncogenic function might be associated with their well-established role in the maintenance of embryonic and adult stem cells. In this review, we discuss new insights into the possible mechanisms by which PcGs regulate cellular identity, and speculate how these functions might be relevant during tumorigenesis.
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                Author and article information

                Journal
                Sci Transl Med
                Science translational medicine
                American Association for the Advancement of Science (AAAS)
                1946-6242
                1946-6234
                Feb 22 2017
                : 9
                : 378
                Affiliations
                [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.
                Article
                9/378/eaai8312
                10.1126/scitranslmed.aai8312
                28228601
                715c6e8e-c074-47ce-a0e9-d807315c7972
                History

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