Role of androgen receptor and associated lysine-demethylase coregulators, LSD1 and JMJD2A, in localized and advanced human bladder cancer

• Published in: Molecular carcinogenesis 2011-12, Vol.50 (12), p.931-944
• Main Authors: Kauffman, Eric C., Robinson, Brian D., Downes, Martin J., Powell, Leagh G., Lee, Ming Ming, Scherr, Douglas S., Gudas, Lorraine J., Mongan, Nigel P.
• Format: Article
• Language: English
• Subjects: Adult; Aged; Aged, 80 and over; Biomarkers, Tumor - biosynthesis; Biomarkers, Tumor - metabolism; Bladder cancer; Cell Line, Tumor; Cell Proliferation - drug effects; epigenetic; Female; Histone Demethylases - antagonists & inhibitors; Histone Demethylases - biosynthesis; Histone Demethylases - metabolism; histone lysine methylation; Humans; Jumonji Domain-Containing Histone Demethylases - biosynthesis; Jumonji Domain-Containing Histone Demethylases - metabolism; Lymphatic Metastasis; Male; Middle Aged; Monoamine Oxidase Inhibitors - pharmacology; Neoplasm Invasiveness; Pargyline - pharmacology; Receptors, Androgen - biosynthesis; Receptors, Androgen - metabolism; Tranylcypromine - pharmacology; Urinary Bladder - metabolism; Urinary Bladder - pathology; Urinary Bladder Neoplasms - metabolism; Urinary Bladder Neoplasms - mortality; Urinary Bladder Neoplasms - pathology; urothelium
• ISSN: 0899-1987; 1098-2744
• DOI: 10.1002/mc.20758

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. © 2011 Wiley Periodicals, Inc.