Department of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul 120-752, Republic of Korea.
Sci Rep. 2017 Mar 24;7:45300. doi: 10.1038/srep45300.
The incidence of prostate cancer (PC) is growing rapidly throughout the world, in probable association with the adoption of western style diets. Thus, understanding the molecular pathways triggering the development of PC is crucial for both its prevention and treatment. Here, we investigated the role of the metabolism-associated protein, CREB3L4, in the proliferation of PC cells. CREB3L4 was upregulated by the synthetic androgen, R1881, in LNCaP PC cells (an androgen-dependent cell line). Knockdown of CREB3L4 resulted in decreased androgen-dependent PC cell growth. LNCaP cells transfected with siCREB3L4 underwent G2/M arrest, with upregulation of the proteins cyclin B1, phospho-CDK1, p21, and INCA1, and downregulation of cyclin D1. Moreover, depletion of CREB3L4 resulted in significantly decreased expression of a subset of androgen-receptor (AR) target genes, including PSA, FKBP5, HPGD, KLK2, and KLK4. We also demonstrated that CREB3L4 directly interacts with the AR, and increases the binding of AR to androgen response elements (AREs). We also identified a role for the unfolded protein response (and its surrogate, IRE1α), in activating CREB3L4. Cumulatively, we postulate that CREB3L4 expression is mediated by an AR-IRE1α axis, but is also directly regulated by AR-to-ARE binding. Thus, our study demonstrates that CREB3L4 plays a key role in PC cell proliferation, which is promoted by both AR and IRE1α.
前列腺癌（PC）的发病率在全球范围内迅速增长，可能与采用西方饮食方式有关。因此，了解触发 PC 发展的分子途径对于其预防和治疗都至关重要。在这里，我们研究了代谢相关蛋白 CREB3L4 在 PC 细胞增殖中的作用。合成雄激素 R1881 可上调 LNCaP PC 细胞（雄激素依赖性细胞系）中的 CREB3L4。 CREB3L4 的敲低导致雄激素依赖性 PC 细胞生长减少。转染 siCREB3L4 的 LNCaP 细胞经历 G2/M 期阻滞，cyclin B1、磷酸化 CDK1、p21 和 INCA1 蛋白上调，cyclin D1 下调。此外， CREB3L4 的耗竭导致一组雄激素受体（AR）靶基因的表达显著下调，包括 PSA、FKBP5、HPGD、KLK2 和 KLK4。我们还证明 CREB3L4 与 AR 直接相互作用，并增加 AR 与雄激素反应元件（AREs）的结合。我们还确定了未折叠蛋白反应（及其替代物 IRE1α）在激活 CREB3L4 中的作用。总之，我们假设 CREB3L4 的表达受 AR-IRE1α 轴介导，但也受 AR 与 ARE 结合的直接调节。因此，我们的研究表明， CREB3L4 在 PC 细胞增殖中起关键作用，这是由 AR 和 IRE1α 共同促进的。
