Histone deacetylase inhibitors , valproic acid and trichostatin-A induce apoptosis and affect acetylation status of p 53 in ERG-positive prostate cancer cells

Content Provider	Semantic Scholar
Author	Fortson, Wendell S. Kayarthodi, Shubhalaxmi Fujimura, Yasuo Hua-Li, Xu Matthews, Roland Grizzle, William E. Rao, V. Narayan Bhat, Ganapathy K. Reddy, E. Shyam P.
Copyright Year	2011
Abstract	An ETS family member, ETS Related Gene (ERG) is involved in the Ewing family of tumors as well as leukemias. Rearrangement of the ERG gene with the TMPRSS2 gene has been identified in the majority of prostate cancer patients. Additionally, overexpression of ERG is associated with unfavorable prognosis in prostate cancer patients similar to leukemia patients. Histone acetyltransferases (HATs) and histone deacetylases (HDACs) regulate transcription as well as epigenetic status of genes through acetylation of both histones and transcription factors. Deregulation of HATs and HDACs is frequently seen in various cancers, including prostate cancer. Many cellular oncogenes as well as tumor viral proteins are known to target either or both HATs and HDACs. Several studies have demonstrated that there are alterations of HDAC activity in prostate cancer cells. Recently, we found that ERG binds and inhibits HATs, which suggests that ERG is involved in deregulation of protein acetylation. Additionally, it has been shown that ERG is associated with a higher expression of HDACs. In this study, we tested the effect of the HDAC inhibitors valproic acid (VPA) and trichostatin-A (TSA) on ERG-positive prostate cancer cells (VCaP). We found that VPA and TSA induce apoptosis, upregulate p21/Waf1/CIP1, repress TMPRSS2-ERG expression and affect acetylation status of p53 in VCaP cells. These results suggest that HDAC inhibitors might restore HAT activity through two different ways: by inhibiting HDAC activity and by repressing HAT targeting oncoproteins such as ERG. Introduction ERG (Ets Related Gene) belongs to the ETS family of transcriptional factors, which shares a homologous 84 amino acids DNA binding domain (1,2). ERG gene codes for sequence specific DNA binding proteins that function as transcriptional activators (3,4). ERG gene is rearranged in Ewing family of tumors and also in leukemias (5-9). ERG gene and its fusion genes (EWS-ERG and TLS/FUS-ERG) code for sequence specific transcriptional activators (7,8). It appears that fusion of RNA binding proteins (EWS and TLS/FUS) with DNA binding proteins (ERG and Fli-1) leads to human cancers (7,8,10,11). These fusion proteins were shown to inhibit apoptosis, which may be one of the reasons for the activation of the ERG gene in leukemias and human solid tumors (12). Rearrangement of ERG is also observed in prostate cancer (13). Among genetic alterations associated with prostate cancer, the rearrangement between the androgen responsive trans-membrane protease serine 2 (TMPRSS2) and transcriptional factor ERG has been detected in approximately 50% of patients (13). This rearrangement results in overexpression of ERG (14-17). TMPRSS2 also fuses with other ETS genes, namely ETV1 (ER81), ETV4 (PEA3) and ETV5; however, they are less common in prostate cancers (15,18,19). ERG is involved in numerous roles in the developmental processes of neural crest, angiogenesis/ vasculogenesis, hematogenesis, and chondrogenesis (20-24). Overexpression of normal or aberrant ERG is associated with transformation, antiapoptotic property, and invasiveness (12,25-28). In prostate cancer, the majority of TMPRSS2-ERG rearrangements produce truncated ERG proteins (29,30). The expression of the chimeric protein, TMPRSS2-ERG, in which the first five amino acids of TMPRSS2 are fused to truncated ERG is associated with early PSA recurrences and seminal vesicle invasion. Additionally, chimeric TMPRSS2-ERG mRNA which translates into full length ERG proteins, is associated with aggressive phenotypes (29). Several studies suggest that an overexpression of ERG alone is responsible for inducing epithelial hyperplasia and prostatic intraepithelial Histone deacetylase inhibitors, valproic acid and trichostatin-A induce apoptosis and affect acetylation status of p53 in ERG-positive prostate cancer cells WENDELL S. FORTSON1, SHUBHALAXMI KAYARTHODI1, YASUO FUJIMURA1, HUALI XU1, ROLAND MATTHEWS1, WILLIAM E. GRIZZLE2, VEENA N. RAO1, GANAPATHY K. BHAT1 and E. SHYAM P. REDDY1 1Cancer Biology Program, Department of OB/GYN, Morehouse School of Medicine, Georgia Cancer Center for Excellence, Grady Health System, 80 Jessie Hill Jr. Drive, Atlanta, GA 30303; 2Department of Pathology, University of Alabama, Birmingham, AL 35294, USA Received February 4, 2011; Accepted March 8, 2011 DOI: 10.3892/ijo.2011.1014 Correspondence to: Professor E. Shyam P. Reddy, Department of OB/GYN, Morehouse School of Medicine, Georgia Cancer Center for Excellence, RM 10C009, Grady Health System, 80 Jesse Hill Jr. Drive, Atlanta, GA 30303-3031, USA E-mail: ereddy@msm.edu
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