Abstract 4295: ASF1B promotes cell proliferation and regulates cell cycle in human benign prostate hyperplasia (BPH)

Abstract

Abstract Background Benign Prostate Hyperplasia (BPH) is enlargement of the prostate, which occurs in 50% men above 50 years of age. Alpha-adrenergic blockers and 5-alpha-reductase inhibitors are the standard medical therapy for BPH. However, these treatments are not only partially effective but also cause significant toxicity in patients. Understanding the molecular pathogenesis of BPH may reveal novel preventive or therapeutic targets for BPH. Methods Normal Human Prostate Epithelial Cells (HPrEpC), RWPE-1 and Benign Prostate Hyperplasia (BPH) were utilized for global sequencing and molecular studies. Western blot analysis was performed to determine the expression of G0/G1 and S-phase and M phase regulators of the cell cycle in BPH and RWPE-1 lysates. Cell cycle and western blot analysis was performed at successive time-points post starvation to understand the dynamics of cell cycle progression in both the cell lines. Knock out experiments were conducted to understand the function ASF1B in normal and BPH cells. Results RNA sequencing analysis revealed that the level of ASF1b (Anti-Silencing Function 1B Histone Chaperone) was over 80 times upregulated in BPH cells as compared to healthy prostate epithelial cells. Induction of ASF1B is specific to BPH as confirmed at protein levels. Induction of ASF1B expression correlated in a time-dependent manner with the increased expression of G1 (cdk4, 6 and cyclin D), G1-S (cdk2) and S-phase (cdk2 and cyclin-A) regulators at both transcription and translation levels. The G1-S phase transcriptional enhancers such as E2-F1 were also upregulated with successive time-points. The cell cycle analysis at sequential time-points revealed that the BPH cells entry to S phase was achieved earlier and by higher fraction of cells than the healthy prostate epithelial cells. Knocking down ASF1B expression by siRNA inhibited the proliferation of BPH cells by 30%. The findings so far suggest that ASF1B might be related to hyper-proliferation in BPH cells. The results indicate that ASF1B might be a novel therapeutic target for preventing hyper-proliferation in BPH. Studies are ongoing to validate the expression of ASF1B in clinical samples along with screening of small molecules targeting ASF1B expression specifically. Current study may lead to identification of a novel preventive and/or therapeutic target and related treatment for BPH. Conclusion Our studies suggest that ASF1b is a G1 and S phase regulator which are critical phases for hyper-proliferative BPH cells. Citation Format: Nisha Dahiya Rani, Dr. Murali Ankem, Dr. Chendil Damodaran. ASF1B promotes cell proliferation and regulates cell cycle in human benign prostate hyperplasia (BPH) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4295.