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

Author

Listed:
  • 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
    Soochow University)

  • 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
    National University Hospital
    National University Hospital)

  • Boon Cher Goh

    (National University of Singapore
    National University Hospital
    National University of Singapore)

  • H. Phillip Koeffler

    (National University of Singapore
    Cedars-Sinai Medical Center
    National University Hospital)

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.

Suggested Citation

  • 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 & Ya, 2019. "Bromodomain and extraterminal proteins foster the core transcriptional regulatory programs and confer vulnerability in liposarcoma," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09257-z
    DOI: 10.1038/s41467-019-09257-z
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    Cited by:

    1. Shigekazu Murakami & Shannon M. White & Alec T. McIntosh & Chan D. K. Nguyen & Chunling Yi, 2023. "Spontaneously evolved progenitor niches escape Yap oncogene addiction in advanced pancreatic ductal adenocarcinomas," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

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