Stearoyl CoA desaturase (SCD) facilitates proliferation of prostate cancer cells through enhancement of androgen receptor transactivation
Stearoyl CoA desaturase (SCD) facilitates proliferation of prostate cancer cells through enhancement of androgen receptor transactivation
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DOI：
10.1007/s10059-011-0043-5
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发表时间：
2011-04-01
影响因子：
3.8
通讯作者：
Kim, Eungseok
中科院分区：
文献类型：
--
作者：
Kim, Seung-Jin;Choi, Hojung;Kim, Eungseok
硬脂酰辅酶a去饱和酶（SCD）是单不饱和脂肪酸生物合成中的限速酶，在前列腺癌中高度表达，尽管已知SCD蛋白可以通过蛋白水解裂解迅速转化。目前的数据表明，SCD可以促进雄激素受体（AR）阳性LNCaP前列腺癌细胞的增殖，增强双氢睾酮（DHT）诱导的AR转录活性，导致前列腺特异性抗原（PSA）和钾likrein相关肽酶2 （KLK2）的表达增加。有趣的是，在先前报道的由SCD蛋白水解裂解产生的SCD衍生肽中，SCD的一个跨越氨基酸130-162的肽（SCD-CoRNR）含有CoRNR框基序（LFLII）并增强了AR转录活性。相比之下，被Ala取代Leu136的突变体SCD-CoRNR对AR的转录活性没有影响。此外，SCD-CoRNR直接与AR相互作用，抑制RIP140对AR转激活的抑制。SCD microRNA敲低SCD基因可抑制AR反激活，降低细胞增殖，提示SCD可能通过调节AR转录活性来调节LNCaP细胞的增殖。此外，SCD在LNCaP细胞中的异位表达促进了LNCaP肿瘤在裸鼠体内的形成和生长。综上所述，这些数据表明，SCD在前列腺癌细胞的AR转录活性调控中起着关键作用。
Stearoyl-CoA desaturase (SCD), the rate-limiting enzyme in the biosynthesis of monounsaturated fatty acids, is highly expressed in prostate cancer although the SCD protein has been known to be rapidly turned over by proteolytic cleavage. The present data demonstrate that SCD can promote proliferation of androgen receptor (AR)-positive LNCaP prostate cancer cells and enhance dihydrotestosterone (DHT)-induced AR transcriptional activity, resulting in increased expression of prostate-specific antigen (PSA) and kallikrein-related peptidase 2 (KLK2). Interestingly, among the previously reported SCD-derived peptides produced by proteolytic cleavage of SCD, a peptide spanning amino acids 130-162 of SCD (SCD-CoRNR) contained the CoRNR box motif (LFLII) and enhanced AR transcriptional activity. In contrast, a mutant SCD-CoRNR in which Leu136 was replaced by Ala had no effect on AR transcriptional activity. Moreover, SCD-CoRNR directly interacted with AR and inhibited RIP140 suppression of AR transactivation. Knockdown of the SCD gene by SCD microRNA suppressed AR transactivation with decreased cell proliferation, suggesting that SCD may regulate the proliferation of LNCaP cells via modulation of AR transcriptional activity. Moreover, ectopic expression of SCD in LNCaP cells facilitated LNCaP tumor formation and growth in nude mice. Together, the data indicate that SCD plays a key role in the regulation of AR transcriptional activity in prostate cancer cells.