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

Nat Commun. 2019 Mar 22;10(1):1353. doi: 10.1038/s41467-019-09257-z.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Azepines / pharmacology
  • Base Sequence
  • Carcinogenesis / genetics
  • Carcinogenesis / pathology
  • Cell Line, Tumor
  • Enhancer Elements, Genetic / genetics
  • Genome, Human
  • Humans
  • Liposarcoma / genetics*
  • Mice, Inbred NOD
  • Mice, SCID
  • Neoplasm Proteins / metabolism*
  • Oncogene Proteins, Fusion / metabolism
  • Thalidomide / analogs & derivatives
  • Thalidomide / pharmacology
  • Transcription, Genetic* / drug effects


  • ARV-825
  • Azepines
  • FUS-DDIT3 fusion protein, human
  • Neoplasm Proteins
  • Oncogene Proteins, Fusion
  • Thalidomide