Loss of an Androgen-Inactivating and Isoform-Specific HSD17B4 Splice Form Enables Emergence of Castration-Resistant Prostate Cancer.
Loss of an Androgen-Inactivating and Isoform-Specific HSD17B4 Splice Form Enables Emergence of Castration-Resistant Prostate Cancer.
复制标题
DOI：
10.1016/j.celrep.2017.12.081
复制
发表时间：
2018-01-16
期刊：
影响因子：
8.8
通讯作者：
Sharifi N
中科院分区：
文献类型：
--
作者：
Ko HK;Berk M;Chung YM;Willard B;Bareja R;Rubin M;Sboner A;Sharifi N
去势抵抗性前列腺癌（CRPC）需要肿瘤参与代谢机制，允许持续的睾酮和/或双氢睾酮刺激进展。由HSD17B4编码的17β-羟素脱氢酶4 （17βHSD4）被认为通过将睾酮和双氢睾酮转化为各自的惰性17-酮类类固醇来灭活睾酮和双氢睾酮。与直觉相反，HSD17B4在CRPC中表达增加，预示预后不良。在这里，我们表明，在五种可选择的剪接形式中，只有异构体2编码一种能够使睾酮和双氢睾酮失活的酶。与其他转录物相比，亚型2的功能性表达在患者CRPC的发展中被特异性抑制。基因沉默异构体2使代谢平衡转向17β-OH雄激素（睾酮和双氢睾酮），刺激雄激素受体（AR）和CRPC的发育。我们的研究明确表明HSD17B4亚型2的丢失与致死性前列腺癌有关。去势抵抗性前列腺癌（CRPC）依赖于维持肿瘤雄激素的代谢过程，这通常需要雄激素合成酶。Ko等人的研究表明，在CRPC中丢失了一种单一的雄激素失活酶剪接形式，并编码唯一阻断雄激素作用和致命疾病的酶。
Castration-resistant prostate cancer (CRPC) requires tumors to engage metabolic mechanisms that allow sustained testosterone and/or dihydrotestosterone to stimulate progression. 17β-Hydroxyste-roid dehydrogenase type 4 (17βHSD4), encoded by HSD17B4, is thought to inactivate testosterone and dihydrotestosterone by converting them to their respective inert 17-keto steroids. Counterintuitively, HSD17B4 expression increases in CRPC and predicts poor prognosis. Here, we show that, of five alternative splice forms, only isoform 2 encodes an enzyme capable of testosterone and dihydrotestosterone inactivation. In contrast with other transcripts, functional expression of isoform 2 is specifically suppressed in development of CRPC in patients. Genetically silencing isoform 2 shifts the metabolic balance toward 17β-OH androgens (testosterone and dihydrotestosterone), stimulating androgen receptor (AR) and CRPC development. Our studies specifically implicate HSD17B4 isoform 2 loss in lethal prostate cancer. Castration-resistant prostate cancer (CRPC) is dependent on metabolic processes that enable sustained tumor androgens, which generally require androgen-synthesizing enzymes. Ko et al. show that a single androgen inactivation enzyme splice form is lost in CRPC and encodes the only enzyme that otherwise blocks androgen action and lethal disease.
登录
查看更多内容
影响因子：
10.9
作者：
Knudsen, Karen E.;Penning, Trevor M.
通讯作者：
Penning, Trevor M.
DOI：
10.1016/j.beem.2008.01.008
发表时间：
2008-04-01
影响因子：
7.4
作者：
Luu-The, Van;Belanger, Alain;Labrie, Fernand
通讯作者：
Labrie, Fernand
影响因子：
64.5
作者：
Chang KH;Li R;Kuri B;Lotan Y;Roehrborn CG;Liu J;Vessella R;Nelson PS;Kapur P;Guo X;Mirzaei H;Auchus RJ;Sharifi N
通讯作者：
Sharifi N
影响因子：
64.8
作者：
Li Z;Bishop AC;Alyamani M;Garcia JA;Dreicer R;Bunch D;Liu J;Upadhyay SK;Auchus RJ;Sharifi N
通讯作者：
Sharifi N
影响因子：
82.9
作者：
Beltran H;Prandi D;Mosquera JM;Benelli M;Puca L;Cyrta J;Marotz C;Giannopoulou E;Chakravarthi BV;Varambally S;Tomlins SA;Nanus DM;Tagawa ST;Van Allen EM;Elemento O;Sboner A;Garraway LA;Rubin MA;Demichelis F
通讯作者：
Demichelis F