Combining BET and HDAC inhibitors synergistically induces apoptosis of melanoma and suppresses AKT and YAP signaling

• DOI: 10.18632/oncotarget.4242
• Publication Date: 2015-09-15T04:49:54Z
• Authors: Anja Heinemann; Carleen Cullinane; Ricardo De Paoli-...; James S. Wilmott; Dilini Gunatilake; Jason Madore; Dario Strbenac; Jean Y. Yang; Kavitha Gowrishankar; Jessamy C. Tiffen; Rab K. Prinjha; Nicholas Smithers; Grant A. McArthur; Peter Hersey; Stuart J. Gallagher
• Keywords: Panobinostat

// Anja Heinemann 1, 2, 3 , Carleen Cullinane 4 Ricardo De Paoli-Iseppi 5 James S. Wilmott Dilini Gunatilake Jason Madore Dario Strbenac 6 Jean Y. Yang Kavitha Gowrishankar 2 Jessamy C. Tiffen Rab K. Prinjha 7 Nicholas Smithers Grant A. McArthur Peter Hersey Stuart J. Gallagher 1 Melanoma Research Group, Kolling Institute of Medical Research, University Sydney, St Leonards NSW, Australia Australia, North Immunology and Oncology Centenary Institute, Camperdown, Translational Laboratory, MacCallum Cancer Centre, Melbourne, VIC, Sydney School, School Mathematics Statistics, Epinova Discovery Performance Unit, GlaxoSmithKline, Stevenage, United Kingdom Correspondence to: Gallagher, e-mail: [e-mail] Keywords: panobinostat, I-BET151, melanoma, bromodomain, epigenetic Received: February 17, 2015 Accepted: May 23, Published: June 05, ABSTRACT Histone acetylation marks have an important role in controlling gene expression are removed by histone deacetylases (HDACs). These read bromodomain extra-terminal (BET) proteins novel inhibitiors these currently clinical development. Inhibitors HDAC BET individually been shown to cause apoptosis reduce growth melanoma cells. Here we show that combining the inhibitor LBH589 I-BET151 synergistically induce cells but not melanocytes. Induction proceeded through mitochondrial pathway, was caspase dependent involved upregulation BH3 pro-apoptotic protein BIM. Analysis signal pathways cell lines resistant BRAF inhibitors revealed treatment with combination strongly downregulated anti-apoptotic AKT Hippo/YAP signaling pathways. Xenograft studies showed more effective than single drug confirmed BIM downregulation XIAP as seen vitro . results support two classes regulators including those inhibitors.