Functional Silencing of HSD17B2 in Prostate Cancer Promotes Disease Progression.
Functional Silencing of HSD17B2 in Prostate Cancer Promotes Disease Progression.
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前列腺癌中 HSD17B2 的功能性沉默促进疾病进展
DOI：
10.1158/1078-0432.ccr-18-2392
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发表时间：
2019-02-15
期刊：
影响因子：
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通讯作者：
Li Z
中科院分区：
文献类型：
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作者：
Gao X;Dai C;Huang S;Tang J;Chen G;Li J;Zhu Z;Zhu X;Zhou S;Gao Y;Hou Z;Fang Z;Xu C;Wang J;Wu D;Sharifi N;Li Z
目的：甾体生成酶是前列腺癌发展的必需酶。酶灭活强效雄激素没有深入研究，这导致有限的干扰策略，前列腺癌治疗。本文探讨HSD17B2酶在前列腺癌发生发展中的临床意义及调控机制。实验设计：用患者标本和前列腺癌细胞系检测HSD17B2的表达。用前列腺癌细胞系和异种移植模型研究了HSD17B2在甾体生成、雄激素受体（AR）信号传导和肿瘤生长中的作用。研究了DNA甲基化和mRNA选择性剪接，揭示了HSD17B2调控的机制。结果：HSD17B2表达随前列腺癌进展而降低。17βHSD2通过将睾酮(T)或二氢睾酮（DHT）转化为它们的上游前体来减少雄激素的产生。HSD17B2过表达抑制雄激素诱导的细胞增殖和异种移植物生长。HSD17B2功能沉默涉及多种机制，包括DNA甲基化和mRNA选择性剪接。DNA甲基化降低HSD17B2 mRNA水平。通过选择性剪接产生的两个新的催化缺陷异构体与野生型17βHSD2结合并促进其降解。剪接因子SRSF1和SRSF5参与了新异构体的产生。结论：我们的研究结果为HSD17B2在前列腺癌进展中的临床相关性、意义和调控提供了证据，针对HSD17B2的功能沉默机制可能为临床治疗提供新的策略。参见Mostaghel的相关评论，第1139页
Purpose: Steroidogenic enzymes are essential for prostate cancer development. Enzymes inactivating potent androgens were not investigated thoroughly, which leads to limited interference strategies for prostate cancer therapy. Here we characterized the clinical relevance, significance, and regulation mechanism of enzyme HSD17B2 in prostate cancer development. Experimental Design: HSD17B2 expression was detected with patient specimens and prostate cancer cell lines. Function of HSD17B2 in steroidogenesis, androgen receptor (AR) signaling, and tumor growth was investigated with prostate cancer cell lines and a xenograft model. DNA methylation and mRNA alternative splicing were investigated to unveil the mechanisms of HSD17B2 regulation. Results: HSD17B2 expression was reduced as prostate cancer progressed. 17βHSD2 decreased potent androgen production by converting testosterone (T) or dihydrotestosterone (DHT) to each of their upstream precursors. HSD17B2 overexpression suppressed androgen-induced cell proliferation and xenograft growth. Multiple mechanisms were involved in HSD17B2 functional silencing including DNA methylation and mRNA alternative splicing. DNA methylation decreased the HSD17B2 mRNA level. Two new catalytic-deficient isoforms, generated by alternative splicing, bound to wild-type 17βHSD2 and promoted its degradation. Splicing factors SRSF1 and SRSF5 participated in the generation of new isoforms. Conclusions: Our findings provide evidence of the clinical relevance, significance, and regulation of HSD17B2 in prostate cancer progression, which might provide new strategies for clinical management by targeting the functional silencing mechanisms of HSD17B2. See related commentary by Mostaghel, p. 1139