Oncotarget

Research Papers:

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

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 _ and Zhengping Zhuang

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Oncotarget. 2017; 8:56110-56125. https://doi.org/10.18632/oncotarget.18125

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Abstract

Chao Zhang1,2,*, Chunzhang Yang3,*, Michael J. Feldman4, Herui Wang4, Ying Pang2, Dominic M. Maggio4, Dongwang Zhu4, Cody L. Nesvick4, Pauline Dmitriev4, Petra Bullova2,5, Prashant Chittiboina4, Roscoe O. Brady4, Karel Pacak2 and Zhengping Zhuang4

1 Department of Orthopedics, Xinqiao Hospital, The Third Military Medical University, Chongqing, China

2 Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, Maryland, USA

3 Neuro-Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA

4 Surgical Neurology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA

5 Department of Molecular Medicine, Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovakia

* These authors have contributed equally to this work

Correspondence to:

Karel Pacak, email:

Zhengping Zhuang, email:

Keywords: HDACi, Hsp90, SAHA, HIF, hypoxia

Received: December 14, 2016 Accepted: April 10, 2017 Published: May 23, 2017

Abstract

Histone deacetylase inhibitors (HDACis) are a potent class of tumor-suppressive agents traditionally believed to exert their effects through loosening tightly-wound chromatin resulting in de-inhibition of various tumor suppressive genes. Recent literature however has shown altered intratumoral hypoxia signaling with HDACi administration not attributable to changes in chromatin structure. We sought to determine the precise mechanism of HDACi-mediated hypoxia signaling attenuation using vorinostat (SAHA), an FDA-approved class I/IIb/IV HDACi. Through an in-vitro and in-vivo approach utilizing cell lines for hepatocellular carcinoma (HCC), osteosarcoma (OS), and glioblastoma (GBM), we demonstrate that SAHA potently inhibits HIF-a nuclear translocation via direct acetylation of its associated chaperone, heat shock protein 90 (Hsp90). In the presence of SAHA we found elevated levels of acetyl-Hsp90, decreased interaction between acetyl-Hsp90 and HIF-a, decreased nuclear/cytoplasmic HIF-α expression, absent HIF-α association with its nuclear karyopharyin Importin, and markedly decreased HIF-a transcriptional activity. These changes were associated with downregulation of downstream hypoxia molecules such as endothelin 1, erythropoietin, glucose transporter 1, and vascular endothelial growth factor. Findings were replicated in an in-vivo Hep3B HRE-Luc expressing xenograft, and were associated with significant decreases in xenograft tumor size. Altogether, this study highlights a novel mechanism of action of an important class of chemotherapeutic.


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