Department of Urology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu 210009, P.R. China.
Department of Urology, Xuzhou Central Hospital, Xuzhou, Jiangsu 221009, P.R. China.
Oncol Rep. 2017 Sep;38(3):1621-1628. doi: 10.3892/or.2017.5852. Epub 2017 Jul 25.
Prostate cancer (PCa) is a leading cause of death among men. The dysregulation of metabolism and autophagy contributes to the progression of PCa. The transcription factor specificity protein 1 (Sp1) is implicated in the regulation of metabolism and autophagy. We confirmed that Sp1 is overexpressed in castration-resistant prostate cancer (CRPC) cells. However, the roles of Sp1 in PCa metabolism and autophagy remain unclear. Thus, in the present study, we retrieved the GSE35988 dataset from Gene Expression Omnibus (GEO) database to reinvestigate Sp1 expression and its role in PCa.We found that in PCa, Sp1 knockdown significantly inhibited cell growth, aerobic glycolysis, and hypoxia-induced autophagy, which were accompanied by an increased G1 cell cycle arrest. Pearson correlation indicated that pyruvate kinase isoenzyme type M2 (PKM2) is positively correlated with Sp1 expression. Western blot analysis demonstrated that Sp1 directly regulates PKM2; therefore, Sp1 modulates metabolism and autophagy in CRPC. Western blot analysis and luciferase reporter assay also indicated that the tumor suppressor miR-361-5p inversely regulates Sp1 by directly targeting the binding site in the 3'UTR of Sp1. miR-361-5p overexpression presented effects that are similar to Sp1 depletion in PCa. In summary, this study is the first to demonstrate that miR-361-5p suppresses the Sp1/PKM2 axis, consequently affecting the progression of PCa and the metabolism and autophagy of PCa cells. Therefore, targeting the miR-361-5p/Sp1/PKM2 pathway has considerable clinical significance in preventing the malignant progression of PCa.
前列腺癌 (PCa) 是男性死亡的主要原因之一。代谢和自噬的失调导致 PCa 的进展。转录因子特异性蛋白 1 (Sp1) 参与代谢和自噬的调节。我们证实 Sp1 在去势抵抗性前列腺癌 (CRPC) 细胞中过表达。然而，Sp1 在 PCa 代谢和自噬中的作用仍不清楚。因此，在本研究中，我们从基因表达综合数据库 (GEO) 中检索了 GSE35988 数据集，以重新研究 Sp1 的表达及其在 PCa 中的作用。我们发现，在 PCa 中，Sp1 敲低显著抑制细胞生长、有氧糖酵解和缺氧诱导的自噬，同时伴有 G1 细胞周期阻滞增加。Pearson 相关性分析表明，丙酮酸激酶同工酶 M2 (PKM2) 与 Sp1 表达呈正相关。Western blot 分析表明 Sp1 直接调节 PKM2；因此，Sp1 调节 CRPC 中的代谢和自噬。Western blot 分析和荧光素酶报告基因 assay 也表明，肿瘤抑制 miR-361-5p 通过直接靶向 Sp1 3'UTR 中的结合位点反向调节 Sp1。miR-361-5p 过表达在 PCa 中呈现出类似于 Sp1 耗竭的效果。总之，本研究首次证明 miR-361-5p 抑制 Sp1/PKM2 轴，进而影响 PCa 的进展以及 PCa 细胞的代谢和自噬。因此，靶向 miR-361-5p/Sp1/PKM2 通路在预防 PCa 的恶性进展方面具有重要的临床意义。
