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 RXRα transcriptional 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 RXRα activity. 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 RXRα transcriptional 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 RXRα transcriptional activity and also inhibits the cell growth. Furthermore, VPA induces apoptosis and restored the expression of RXRα target 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.

Ets Related Gene and Smad3 Proteins Collaborate to Activate Transforming Growth Factor-Beta Mediated Signaling Pathway in ETS Related Gene-Positive Prostate Cancer Cells

“…Recently, Dr. Reddy’s group has shown that antiepileptic drug targets ERG-positive prostate cancer cells through activation of tumor suppressors and nuclear receptors (Fortson, 2011). Similar results were also observed in the Ewing family of tumors (Kayarthodi et al 2014). …”

Therapeutic applications of histone deacetylase inhibitors in sarcoma

“…Retinoid X receptors (RXRs) and retinoic acid receptors (RARs) are nuclear receptors that mediate the biological effects of retinoids by their involvement in retinoic acid-mediated gene activation. HDI valproic acid restored the expression of RXR α target genes RARβ , CRABPII and p21 , and conversely, repressed the expression of fusion oncogenes, EWS-ERG and EWS-Fli1 in Ewing sarcoma cells 29 . Plakoglobin is a member of the catenin protein family and a homologue to β-catenin.…”

Histone deacetylase inhibitor ITF2357 leads to apoptosis and enhances doxorubicin cytotoxicity in preclinical models of human sarcoma

“…HDAC inhibitors (HDACi) have been reported as effective anti-cancer molecules alone or in combination in preclinical 7 , 8 and clinical studies 9 – 11 . In particular, several preclinical studies demonstrated that HDACi alone or in combination therapy constitute novel therapeutics versus different sarcoma histotypes including Ewing 12 , 13 , epithelioid 14 , liposarcoma 15 , synovial and rhabdomyosarcomas 16 – 18 , and osteosarcoma 19 – 23 . HDACi activities have been mainly due to their effect on cell growth and survival, on apoptosis or autophagy, or cancer stem cells 12 , 13 , 15 , 24 – 27 .…”

“…In particular, several preclinical studies demonstrated that HDACi alone or in combination therapy constitute novel therapeutics versus different sarcoma histotypes including Ewing 12 , 13 , epithelioid 14 , liposarcoma 15 , synovial and rhabdomyosarcomas 16 – 18 , and osteosarcoma 19 – 23 . HDACi activities have been mainly due to their effect on cell growth and survival, on apoptosis or autophagy, or cancer stem cells 12 , 13 , 15 , 24 – 27 . On the basis of these preclinical evidences, some HDACi against sarcomas have been moving from phase I to phase II clinical trials alone or in combination anthracyclines 9 , 10 , 28 – 30 .…”