title: Anti-Epileptic Drug Targets Ewing Sarcoma.
abstract: Ewing Sarcoma (ES) is a rare form of bone cancer that most commonly affects children and adolescents. Chromosomal translocations are fundamental to the development of Ewing Sarcoma, linked to the changes in gene expression affecting transcription factors. Histone acetyl transferases (HATs) and histone deacetylases (HDACs) regulate transcription by modifying acetylation of both histones and transcription factors. Despite the use of multimodal therapeutic approaches current therapies are associated with significant short and long-term side effects. Hence, new therapeutic approaches are needed. In this study, we show that ERG/EWS-ERG, inhibits transcriptional activation properties of RXRα. These results suggest that ERG/EWS-ERG/EWS-Fli-1 may target transcriptional co-activators and transcriptional repressors and thereby regulate RXRαtranscriptional activity. To understand the molecular mechanism of action, how the fusion protein targets nuclear receptor function, and to provide a clue for the cancer health disparity seen in Ewing Sarcoma, we hypothesized that the aberrant fusion protein, EWS-ERG/EWS-Fli-1 regulates HDACs-mediated repressor complex and inhibits the binding of transcriptional activator complex causing transcriptional repression of RXRαactivity. Since it is known that HDACs regulate nuclear receptors, we proposed that HDAC inhibitor, valproic acid (VPA), an anti-epileptic drug, may reverse the inhibitory properties of EWS-ERG/EWS-Fli-1 oncoprotein on RXRαtranscriptional activity and might therefore be used as therapeutic agent in ES. We demonstrate that VPA reverses the inhibitory effect of EWSERG/EWS-Fli-1 on RXRαtranscriptional activity and also inhibits the cell growth. Furthermore, VPA induces apoptosis and restored the expression of RXRαtarget genes RARβ, CRABPII and p21 activity and repressed the expression of aberrant fusion proteins, EWS-ERG and EWS-Fli-1 in Ewing Sarcoma cells. Thus, therapeutic regulation of transcriptional repressor properties of EWS-ERG/EWS-Fli-1 with an anti-epileptic drug with a promising new potential might have a profound impact on prevention, management and treatment of Ewing Sarcoma. Therapeutic use of VPA in minority patients may help reduce the health disparity.
authors: Cancer Biology Program, Department of OB/GYN, Morehouse School of Medicine, Georgia Cancer Center for Excellence, Grady Memorial Hospital, 80 Jesse Hill Jr. Drive, Atlanta, 30303, GA.
authors: Shubhalaxmi
authors: S
authors: Kayarthodi
authors: Cancer Biology Program, Department of OB/GYN, Morehouse School of Medicine, Georgia Cancer Center for Excellence, Grady Memorial Hospital, 80 Jesse Hill Jr. Drive, Atlanta, 30303, GA.
authors: Yasuo
authors: Y
authors: Fujimura
authors: Cancer Biology Program, Department of OB/GYN, Morehouse School of Medicine, Georgia Cancer Center for Excellence, Grady Memorial Hospital, 80 Jesse Hill Jr. Drive, Atlanta, 30303, GA.
authors: Jinbo
authors: J
authors: Fang
authors: Cancer Biology Program, Department of OB/GYN, Morehouse School of Medicine, Georgia Cancer Center for Excellence, Grady Memorial Hospital, 80 Jesse Hill Jr. Drive, Atlanta, 30303, GA.
authors: Sharif
authors: S
authors: Morsalin
authors: Cancer Biology Program, Department of OB/GYN, Morehouse School of Medicine, Georgia Cancer Center for Excellence, Grady Memorial Hospital, 80 Jesse Hill Jr. Drive, Atlanta, 30303, GA.
authors: Veena N
authors: VN
authors: Rao
authors: Cancer Biology Program, Department of OB/GYN, Morehouse School of Medicine, Georgia Cancer Center for Excellence, Grady Memorial Hospital, 80 Jesse Hill Jr. Drive, Atlanta, 30303, GA.
authors: E Shyam P
authors: ES
authors: Reddy
keywords: EWS-ERG; EWS-Fli-1; Ewing Sarcoma; Histone Deacetylase; Retinoid X Receptor α; Valproic Acid