A genome scale RNAi screen identifies GLI1 as a novel gene regulating vorinostat sensitivity

KJ Falkenberg; A Newbold; CM Gould; J Luu; JA Trapani; GM Matthews; KJ Simpson; RW Johnstone

Journal article

A genome scale RNAi screen identifies GLI1 as a novel gene regulating vorinostat sensitivity

KJ Falkenberg, A Newbold, CM Gould, J Luu, JA Trapani, GM Matthews, KJ Simpson, RW Johnstone

Cell Death and Differentiation | NATURE PUBLISHING GROUP | Published : 2016

DOI: 10.1038/cdd.2015.175

Abstract

Vorinostat is an FDA-approved histone deacetylase inhibitor (HDACi) that has proven clinical success in some patients; however, it remains unclear why certain patients remain unresponsive to this agent and other HDACis. Constitutive STAT (signal transducer and activator of transcription) activation, overexpression of prosurvival Bcl-2 proteins and loss of HR23B have been identified as potential biomarkers of HDACi resistance; however, none have yet been used to aid the clinical utility of HDACi. Herein, we aimed to further elucidate vorinostat-resistance mechanisms through a functional genomics screen to identify novel genes that when knocked down by RNA interference (RNAi) sensitized cells ..

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University of Melbourne Researchers

Andrea Newbold Author

Joseph Trapani Author

Kaylene Simpson Author

Ricky Johnstone Author

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Defining the apoptotic and therapeutic activities of histone deacetylase inhibitors

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Grants

Awarded by Merck

Funding Acknowledgements

We thank Richard Tothill, Maria Doyle and Jason Ellul for constructive discussions about NGS methodologies and analysis. For technical support, we also thank Yanny Handoko and Daniel Thomas (Victorian Centre for Functional Genomics), Andrea Newbold and Timothy Semple, Timothy Holloway and Aga Borcz (Molecular Genomics Facility). This work was supported by Merck Research Laboratories, and an Australian National Health and Medical Research Council (NHMRC) project grant APP1028871 (to RWJ). KJF was a recipient of an Australian Postgraduate Award and later a Cancer Council Victoria Postdoctoral Research Fellowship. RWJ is a Senior Principal Research Fellow of the National Health and Medical Research Council (NHMRC) of Australia and supported by NHMRC Program and Project Grants, Cancer Council Victoria, the Leukemia Foundation of Australia and the Victorian Cancer Agency. The VCFG (KJS) is funded by the Australian Cancer Research Foundation (ACRF), the Victorian Department of Industry, Innovation and Regional Development (DIIRD), the Australian Phenomics Network (APN) supported by funding from the Australian Government's Education Investment Fund through the Super Science Initiative, the Australasian Genomics Technologies Association (AMATA), the Brockhoff Foundation and the Peter MacCallum Cancer Centre Foundation.