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

被引：189

作者：

Bhadury, Joydeep ^{[1
]}

Nilsson, Lisa M. ^{[1
]}

Muralidharan, Somsundar Veppil ^{[1
]}

Green, Lydia C. ^{[1
]}

Li, Zhoulei ^{[2
]}

Gesner, Emily M. ^{[3
]}

Hansen, Henrik C. ^{[3
]}

Keller, Ulrich B. ^{[2
]}

McLure, Kevin G. ^{[3
]}

Nilsson, Jonas A. ^{[1
]}

机构：

[1] Univ Gothenburg, Inst Clin Sci, Sahlgrenska Canc Ctr, Dept Surg, S-41390 Gothenburg, Sweden

[2] Tech Univ Munich, Dept Med 3, D-81675 Munich, Germany

[3] Zenith Epigenet Corp, Calgary, AB T2L 2K7, Canada

来源：

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA | 2014年 / 111卷 / 26期

基金：

瑞典研究理事会;

关键词：

mouse models; JQ1; vorinostat; Brd2; Brd4; BROMODOMAIN PROTEIN BRD4; HISTONE DEACETYLASE INHIBITORS; ACUTE LYMPHOBLASTIC-LEUKEMIA; ACUTE MYELOID-LEUKEMIA; B-CELL LYMPHOMA; C-MYC; P-TEFB; TRANSCRIPTIONAL ELONGATION; SELECTIVE-INHIBITION; DISRUPTION;

D O I：

10.1073/pnas.1406722111

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

070301 [无机化学]; 070403 [天体物理学]; 070507 [自然资源与国土空间规划学]; 090105 [作物生产系统与生态工程];

摘要：

The bromodomain and extraterminal (BET) domain family of proteins binds to acetylated lysines on histones and regulates gene transcription. Recently, BET inhibitors (BETi) have been developed that show promise as potent anticancer drugs against various solid and hematological malignancies. Here we show that the structurally novel and orally bioavailable BET inhibitor RVX2135 inhibits proliferation and induces apoptosis of lymphoma cells arising in Myc-transgenic mice in vitro and in vivo. We find that BET inhibition exhibits broad transcriptional effects in Myc-transgenic lymphoma cells affecting many transcription factor networks. By examining the genes induced by BETi, which have largely been 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. Our data suggest that BETi sensitize Myc-overexpressing lymphoma cells partly by inducing HDAC-silenced genes, and suggest synergistic and therapeutic combinations by targeting the genetic link between BETi and HDACi.

引用

页码：E2721 / E2730

页数：10

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