Role of androgen receptor and associated lysine‐demethylase coregulators, LSD1 and JMJD2A, in localized and advanced human bladder cancer
- 11 March 2011
- journal article
- research article
- Published by Wiley in Molecular Carcinogenesis
- Vol. 50 (12), 931-944
- https://doi.org/10.1002/mc.20758
Abstract
Bladder cancer is approximately three times more common in men as compared to women. We and others have previously investigated the contribution of androgens and the androgen receptor (AR) to bladder cancer. JMJD2A and LSD1 are recently discovered AR coregulator proteins that mediate AR‐dependent transcription via recently described histone lysine‐demethylation (KDM) mechanisms. We used immunohistochemistry to examine JMJD2A, LSD1, and AR expression in 72 radical cystectomy specimens, resulting in evaluation of 129 tissue samples (59 urothelial carcinoma, 70 benign). We tested levels of these proteins for statistical association with clinicopathologic variables and patient survival. Expression of these markers was also assessed in human bladder cancer cell lines. The effects of pharmacological inhibition of LSD1 on the proliferation of these bladder cancer cells was determined. JMJD2A and AR levels were significantly lower in malignant versus benign urothelium, while increased LSD1 levels were observed in malignant urothelium relative to benign. A significant reduction in all three proteins occurred with cancer stage progression, including muscle invasion (JMJD2A/LSD1/AR), extravesical extension (JMJD2A/LSD1), and lymph node metastasis (JMJD2A/AR). Lower JMJD2A intensity correlated with additional poor prognostic features, including lymphovascular invasion, concomitant carcinoma in situ and tobacco usage, and predicted significantly worse overall survival. Pharmacological inhibition of LSD1 suppressed bladder cancer cell proliferation and androgen‐induced transcription. Our results support a novel role for the AR–KDM complex in bladder cancer initiation and progression, identify JMJD2A as a promising prognostic biomarker, and demonstrate targeting of the KDM activity as an effective potential approach for bladder cancer growth inhibition.Keywords
This publication has 54 references indexed in Scilit:
- Selective Inhibitors of the JMJD2 Histone Demethylases: Combined Nondenaturing Mass Spectrometric Screening and Crystallographic ApproachesJournal of Medicinal Chemistry, 2010
- Novel Oligoamine Analogues Inhibit Lysine-Specific Demethylase 1 and Induce Reexpression of Epigenetically Silenced GenesClinical Cancer Research, 2009
- Androgen receptor is a tumor suppressor and proliferator in prostate cancerProceedings of the National Academy of Sciences of the United States of America, 2008
- Androgen regulation of the androgen receptor coregulatorsBMC Cancer, 2008
- Inhibition of lysine-specific demethylase 1 by polyamine analogues results in reexpression of aberrantly silenced genesProceedings of the National Academy of Sciences of the United States of America, 2007
- Cooperative demethylation by JMJD2C and LSD1 promotes androgen receptor-dependent gene expressionNature, 2007
- Histone H3 Lysine 4 Demethylation Is a Target of Nonselective Antidepressive MedicationsCell Chemical Biology, 2006
- An essential role for CoREST in nucleosomal histone 3 lysine 4 demethylationNature, 2005
- LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcriptionNature, 2005
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001