Role of androgen receptor and associated lysine-demethylase coregulators, LSD1 and JMJD2A, in localized and advanced human bladder cancer.
Role of androgen receptor and associated lysine-demethylase coregulators, LSD1 and JMJD2A, in localized and advanced human bladder cancer.
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DOI：
10.1002/mc.20758
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发表时间：
2011-12
影响因子：
4.6
通讯作者：
Mongan, Nigel P.
中科院分区：
文献类型：
--
作者：
Kauffman, Eric C.;Robinson, Brian D.;Downes, Martin J.;Powell, Leagh G.;Lee, Ming Ming;Scherr, Douglas S.;Gudas, Lorraine J.;Mongan, Nigel P.
膀胱癌在男性中的发病率大约是女性的三倍。我们和其他人先前已经研究了雄激素和雄激素受体（AR）对膀胱癌的作用。JMJD 2A和LSD 1是最近发现的AR辅助调节蛋白，其通过最近描述的组蛋白赖氨酸去甲基化（KDM）机制介导AR依赖性转录。我们使用免疫组织化学方法检测了72例根治性膀胱癌标本中JMJD 2A、LSD 1和AR的表达，从而评估了129例组织样本（59例尿路上皮癌，70例良性）。我们检测了这些蛋白质的水平与临床病理变量和患者生存率的统计学相关性。还在人膀胱癌细胞系中评估了这些标志物的表达。测定LSD 1对这些膀胱癌细胞增殖的药理学抑制作用。JMJD 2A和AR水平在恶性尿道炎中显著低于良性尿道炎，而在恶性尿道炎中观察到LSD 1水平相对于良性尿道炎增加。所有三种蛋白质的显著降低随着癌症阶段进展而发生，包括肌肉浸润（JMJD 2A/LSD 1/AR）、膀胱外延伸（JMJD 2A/LSD 1）和淋巴结转移（JMJD 2A/AR）。较低的JMJD 2A强度与其他不良预后特征相关，包括淋巴管浸润，伴随原位癌和烟草使用，并预测总生存率显着降低。药理学抑制LSD 1抑制膀胱癌细胞增殖和雄激素诱导的转录。我们的研究结果支持AR-KDM复合物在膀胱癌发生和进展中的新作用，将JMJD 2A鉴定为有希望的预后生物标志物，并证明靶向KDM活性作为膀胱癌生长抑制的有效潜在方法。
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.
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影响因子：
254.7
作者：
Jemal, Ahmedin;Siegel, Rebecca;Thun, Michael J.
通讯作者：
Thun, Michael J.
影响因子：
7.3
作者：
Comuzzi, B;Nemes, C;Hobisch, A
通讯作者：
Hobisch, A
影响因子：
2.1
作者：
Boorjian, S;Ugras, S;Scherr, DS
通讯作者：
Scherr, DS
影响因子：
64.8
作者：
Lee, MG;Wynder, C;Shiekhattar, R
通讯作者：
Shiekhattar, R
DOI：
10.1016/j.bbagrm.2008.07.009
发表时间：
2009-01
影响因子：
4.7
作者：
Marmorstein, Ronen;Trievel, Raymond C.
通讯作者：
Trievel, Raymond C.