LSD1 inhibition attenuates androgen receptor V7 splice variant activation in castration resistant prostate cancer models.
LSD1 inhibition attenuates androgen receptor V7 splice variant activation in castration resistant prostate cancer models.
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DOI：
10.1186/s12935-018-0568-1
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发表时间：
2018
影响因子：
5.8
通讯作者：
Crabb SJ
中科院分区：
文献类型：
--
作者：
Regufe da Mota S;Bailey S;Strivens RA;Hayden AL;Douglas LR;Duriez PJ;Borrello MT;Benelkebir H;Ganesan A;Packham G;Crabb SJ
去势抵抗型前列腺癌(CRPC)通常是由雄激素受体的构成活性形式如V7剪接变异体(AR-V7)驱动的，因此通常对现有的激素治疗策略如苯扎鲁胺产生抗药性。赖氨酸去甲基酶LSD1是野生型雄激素受体的共同激活剂，是激素敏感型前列腺癌的潜在治疗靶点。我们评估了LSD1是否也可以在AR-V7驱动的CRPC模型中作为治疗靶点。我们利用AR-V7过表达的去势抵抗前列腺癌的细胞系模型来测试化学LSD1抑制对AR激活的影响。我们通过缺失LSD1表达和在表达AR-V7的前列腺癌细胞系中验证了这一发现。化学抑制LSD1可通过野生型及其AR-V7剪接变异体降低雄激素受体的活性。这在荧光素酶报告分析、LNCaP和22Rv1前列腺癌细胞系以及LSD1耗竭实验中得到了证实和验证。LSD1有助于激活雄激素受体的野生型和V7剪接变体，并可作为CRPC模型的治疗靶点。这种方法的进一步发展是有必要的。本文的在线版本(10.1186/s12935-0180568-1)包含补充材料，可供授权用户使用。
Castrate resistant prostate cancer (CRPC) is often driven by constitutively active forms of the androgen receptor such as the V7 splice variant (AR-V7) and commonly becomes resistant to established hormonal therapy strategies such as enzalutamide as a result. The lysine demethylase LSD1 is a co-activator of the wild type androgen receptor and a potential therapeutic target in hormone sensitive prostate cancer. We evaluated whether LSD1 could also be therapeutically targeted in CRPC models driven by AR-V7. We utilised cell line models of castrate resistant prostate cancer through over expression of AR-V7 to test the impact of chemical LSD1 inhibition on AR activation. We validated findings through depletion of LSD1 expression and in prostate cancer cell lines that express AR-V7. Chemical inhibition of LSD1 resulted in reduced activation of the androgen receptor through both the wild type and its AR-V7 splice variant forms. This was confirmed and validated in luciferase reporter assays, in LNCaP and 22Rv1 prostate cancer cell lines and in LSD1 depletion experiments. LSD1 contributes to activation of both the wild type and V7 splice variant forms of the androgen receptor and can be therapeutically targeted in models of CRPC. Further development of this approach is warranted. The online version of this article (10.1186/s12935-018-0568-1) contains supplementary material, which is available to authorized users.
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影响因子：
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作者：
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通讯作者：
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影响因子：
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影响因子：
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DOI：
10.1056/nejmoa1315815
发表时间：
2014-09-11
期刊：
The New England journal of medicine
影响因子：
--
作者：
Antonarakis ES;Lu C;Wang H;Luber B;Nakazawa M;Roeser JC;Chen Y;Mohammad TA;Chen Y;Fedor HL;Lotan TL;Zheng Q;De Marzo AM;Isaacs JT;Isaacs WB;Nadal R;Paller CJ;Denmeade SR;Carducci MA;Eisenberger MA;Luo J
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