Department of Biological Sciences, College of Natural Sciences, Chonnam National University, Gwangju 500-757, Korea.
Mol Cells. 2011 Apr;31(4):371-7. doi: 10.1007/s10059-011-0043-5. Epub 2011 Feb 10.
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.
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，尽管 SCD 蛋白已被证明会被蛋白水解切割迅速降解，但在前列腺癌中高度表达。本研究数据表明，SCD 可促进雄激素受体（AR）阳性 LNCaP 前列腺癌细胞的增殖，并增强二氢睾酮（DHT）诱导的 AR 转录活性，导致前列腺特异性抗原（PSA）和激肽释放酶相关肽 2（KLK2）的表达增加。有趣的是，在之前报道的 SCD 蛋白经蛋白水解切割产生的 SCD 衍生肽中，一段跨越 SCD 氨基酸 130-162 的肽（SCD-CoRNR）含有 CoRNR 盒基序（LFLII），并增强了 AR 转录活性。相比之下，将 Leu136 替换为 Ala 的突变 SCD-CoRNR 对 AR 转录活性没有影响。此外，SCD-CoRNR 直接与 AR 相互作用，并抑制 RIP140 对 AR 反式激活的抑制作用。SCD 微小 RNA 对 SCD 基因的敲低抑制了 AR 反式激活，同时降低了细胞增殖，这表明 SCD 可能通过调节 AR 转录活性来调节 LNCaP 细胞的增殖。此外，在 LNCaP 细胞中异位表达 SCD 促进了 LNCaP 肿瘤在裸鼠中的形成和生长。综上所述，数据表明 SCD 在前列腺癌细胞中 AR 转录活性的调节中发挥关键作用。
