title: Histone deacetylase inhibitors, valproic acid and trichostatin-A induce apoptosis and affect acetylation status of p53 in ERG-positive prostate cancer cells.
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.
authors.affiliation: Cancer 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, USA.
authors.forename: Wendell S
authors.initials: WS
authors.lastname: Fortson
authors.forename: Shubhalaxmi
authors.initials: S
authors.lastname: Kayarthodi
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Fujimura
authors.forename: Huali
authors.initials: H
authors.lastname: Xu
authors.forename: Roland
authors.initials: R
authors.lastname: Matthews
authors.forename: William E
authors.initials: WE
authors.lastname: Grizzle
authors.forename: Veena N
authors.initials: VN
authors.lastname: Rao
authors.forename: Ganapathy K
authors.initials: GK
authors.lastname: Bhat
authors.forename: E Shyam P
authors.initials: ES
authors.lastname: Reddy
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D019556:COS Cells; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008297:Male; D008954:Models, Biological; D011471:Prostatic Neoplasms / Q000235:genetics / Q000503:physiopathology*; D050783:Proto-Oncogene Proteins c-ets / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014635:Valproic Acid / Q000494:pharmacology*; D054462:p21-Activated Kinases / Q000235:genetics / Q000378:metabolism
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D050783:Proto-Oncogene Proteins c-ets; D016159:Tumor Suppressor Protein p53; C012589:trichostatin A; D014635:Valproic Acid; D054462:p21-Activated Kinases; D053148:Caspase 3; D053179:Caspase 7; D006655:Histone Deacetylases