Vorinostat suppresses hypoxia signaling by modulating nuclear translocation of hypoxia inducible factor 1 alpha

• DOI: 10.18632/oncotarget.18125
• Publication Date: 2017-05-24T07:17:50Z
• Authors: Chao Zhang; Chunzhang Yang; Michael J. Feldman; Herui Wang; Ying Pang; Dominic M. Maggio; Dongwang Zhu; Cody L. Nesvick; Pauline Dmitriev; Petra Bullova; Prashant Chittiboina; Roscoe O. Brady; Karel Pacak; Zhengping Zhuang
• Keywords: Hypoxia; HIF1A; Hypoxia-Inducible Factors; Hypoxia-Inducible Factor 1; Vorinostat; Alpha (finance)

// Chao Zhang 1,2,* , Chunzhang Yang 3,* Michael J. Feldman 4 Herui Wang Ying Pang 2 Dominic M. Maggio Dongwang Zhu Cody L. Nesvick Pauline Dmitriev Petra Bullova 2,5 Prashant Chittiboina Roscoe O. Brady Karel Pacak and Zhengping Zhuang 1 Department of Orthopedics, Xinqiao Hospital, The Third Military Medical University, Chongqing, China Program in Reproductive Adult Endocrinology, Eunice Kennedy Shriver National Institute Child Health Human Development, Bethesda, Maryland, USA 3 Neuro-Oncology Branch, Center for Cancer Research, Institute, Surgical Neurology Neurological Disorders Stroke, Institutes Health, 5 Molecular Medicine, Virology, Slovak Academy Sciences, Bratislava, Slovakia * These authors have contributed equally to this work Correspondence to: Pacak, email: Zhuang, Keywords : HDACi, Hsp90, SAHA, HIF, hypoxia Received December 14, 2016 Accepted April 10, 2017 Published May 23, Abstract Histone deacetylase inhibitors (HDACis) are a potent class tumor-suppressive agents traditionally believed exert their effects through loosening tightly-wound chromatin resulting de-inhibition various tumor suppressive genes. Recent literature however has shown altered intratumoral signaling with HDACi administration not attributable changes structure. We sought determine the precise mechanism HDACi-mediated attenuation using vorinostat (SAHA), an FDA-approved I/IIb/IV HDACi. Through in-vitro in-vivo approach utilizing cell lines hepatocellular carcinoma (HCC), osteosarcoma (OS), glioblastoma (GBM), we demonstrate that SAHA potently inhibits HIF-a nuclear translocation via direct acetylation its associated chaperone, heat shock protein 90 (Hsp90). In presence found elevated levels acetyl-Hsp90, decreased interaction between acetyl-Hsp90 HIF-a, nuclear/cytoplasmic HIF-α expression, absent association karyopharyin Importin, markedly transcriptional activity. were downregulation downstream molecules such as endothelin 1, erythropoietin, glucose transporter vascular endothelial growth factor. Findings replicated Hep3B HRE-Luc expressing xenograft, significant decreases xenograft size. Altogether, study highlights novel action important chemotherapeutic.