Bromodomain and Extraterminal Proteins Foster the Core Transcriptional Regulatory Programs and Confer Vulnerability in Liposarcoma

Overview

Journal Nat Commun

Specialty Biology

Date 2019 Mar 24

PMID 30903020

Citations 33

Authors

Ye Chen

Liang Xu

Anand Mayakonda

Mo-Li Huang

Deepika Kanojia

Tuan Zea Tan

Pushkar Dakle

Ruby Yu-Tong Lin

Xin-Yu Ke

Jonathan W Said

Jianxiang Chen

Sigal Gery

Ling-Wen Ding

Yan-Yi Jiang

Angela Pang

Mark Edward Puhaindran

Boon Cher Goh

H Phillip Koeffler

Affiliations

Soon will be listed here.

Abstract

Liposarcomas (LPSs) are a group of malignant mesenchymal tumors showing adipocytic differentiation. Here, to gain insight into the enhancer dysregulation and transcriptional addiction in this disease, we chart super-enhancer structures in both LPS tissues and cell lines. We identify a bromodomain and extraterminal (BET) protein-cooperated FUS-DDIT3 function in myxoid LPS and a BET protein-dependent core transcriptional regulatory circuitry consisting of FOSL2, MYC, and RUNX1 in de-differentiated LPS. Additionally, SNAI2 is identified as a crucial downstream target that enforces both proliferative and metastatic potentials to de-differentiated LPS cells. Genetic depletion of BET genes, core transcriptional factors, or SNAI2 mitigates consistently LPS malignancy. We also reveal a compelling susceptibility of LPS cells to BET protein degrader ARV-825. BET protein depletion confers additional advantages to circumvent acquired resistance to Trabectedin, a chemotherapy drug for LPS. Moreover, this study provides a framework for discovering and targeting of core oncogenic transcriptional programs in human cancers.

Citing Articles

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