Bromodomain and extraterminal proteins foster the core transcriptional regulatory programs and confer vulnerability in liposarcoma

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 and H. Phillip Koeffler
Additional contact information
Ye Chen: National University of Singapore
Liang Xu: National University of Singapore
Anand Mayakonda: National University of Singapore
Mo-Li Huang: National University of Singapore
Deepika Kanojia: National University of Singapore
Tuan Zea Tan: National University of Singapore
Pushkar Dakle: National University of Singapore
Ruby Yu-Tong Lin: National University of Singapore
Xin-Yu Ke: National University of Singapore
Jonathan W. Said: University of California
Jianxiang Chen: Hangzhou Normal University
Sigal Gery: Cedars-Sinai Medical Center
Ling-Wen Ding: National University of Singapore
Yan-Yi Jiang: National University of Singapore
Angela Pang: National University Hospital
Mark Edward Puhaindran: National University Hospital
Boon Cher Goh: National University of Singapore
H. Phillip Koeffler: National University of Singapore

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-019-09257-z Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09257-z

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-019-09257-z

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().