LncRNA GAS5 Inhibits Cellular Proliferation by Targeting P27^Kip1

Recent studies have demonstrated that long noncoding RNAs (lncRNA) have important roles in cancer biology, and that the downregulation of lncRNA growth arrest-specific transcript 5 (GAS5) has been reported in a variety of human cancers. However, its role in prostate cancer is largely unknown. This study aims to investigate the biological role and underlying mechanism of GAS5 on proliferation in prostate cancer. The results demonstrate that GAS5 expression is significantly decreased in prostate cancer cells compared with prostate epithelial cells. Ectopic expression of GAS5 inhibited cell proliferation and induced a cell-cycle arrest in G₀-G₁ phase, whereas GAS5 knockdown promoted the G₁-S phase transition. Subsequent analysis demonstrated that P27^Kip1, a known regulator of cell cycle, was positively regulated by GAS5 and upregulation of GAS5 increased its promoter activity. E2F1, an important transcription factor, was shown to bind directly to and activate the P27^Kip1 promoter. In addition, GAS5 interacted with E2F1 and enhanced the binding of E2F1 to the P27^Kip1 promoter. Collectively, these findings determine that GAS5 functions as a tumor suppressor in prostate cancer development and progression via targeting P27^Kip1Implications: This study reveals a molecular pathway involving lncRNA GAS5/E2F1/P27^Kip1 which regulates cell proliferation and could be a potential therapeutic target in prostate cancer. Mol Cancer Res; 15(7); 789-99. ©2017 AACR.