Abstract B26: BET and HDAC inhibitors induce similar genes and biological effects and synergize to kill in Myc-induced murine lymphoma

Abstract

Abstract Bromodomain and extraterminal (BET) proteins bind acetylated proteins, including histones, and regulate transcription. Recently, BET inhibitors (BETi) have been developed that show promise as potent anti-cancer drugs against various solid and hematological malignancies. Here we show that the structurally novel and orally bioavailable BETi RVX2135 inhibits proliferation and induces apoptosis of lymphoma cells arising in Myc-transgenic mice, in vitro and in vivo. We find that BET inhibition exhibited broad transcriptional effects in Myc-transgenic lymphoma cells affecting many transcription factor networks. By examining the genes induced by BETi, which have been largely ignored to date, we discovered that these were similar to those induced by histone deacetylase inhibitors (HDACi). HDACi also induced cell cycle arrest and cell death of Myc-induced murine lymphoma cells and synergized with BETi. To date many of the effects of BETi have been attributed to transcriptional suppression of genes like the MYC oncogene. Moreover, global profiling of the expression of miRNAs demonstrated that HDACi and BETi exhibited a very similar miRNA transcriptome. We also show one of the possible mechanism which might leads to the similarity of induced genes by BETi and HDACi using ChIP-sequencing experiments. Finally, we unravel a genetic and functional link between BET proteins and histone deacetylases (HDAC) that opens up avenues for combination therapies against a variety of cancer. Citation Format: Joydeep Bhadury, Lisa M. Nilsson, Muralidharan Veppil Somsundar, Lydia C. Green, Ulrich B. Keller, Kevin G. McLure, Jonas A. Nilsson. BET and HDAC inhibitors induce similar genes and biological effects and synergize to kill in Myc-induced murine lymphoma. [abstract]. In: Proceedings of the AACR Special Conference on Myc: From Biology to Therapy; Jan 7-10, 2015; La Jolla, CA. Philadelphia (PA): AACR; Mol Cancer Res 2015;13(10 Suppl):Abstract nr B26.