Opposing Functions of BRD4 Isoforms in Breast Cancer

Shwu Yuan Wu, Chien Fei Lee, Hsien Tsung Lai, Cheng Tai Yu, Ji Eun Lee, Hao Zuo, Sophia Y. Tsai, Ming Jer Tsai, Kai Ge, Yihong Wan, Cheng Ming Chiang

Research output: Contribution to journalArticle

Abstract

Bromodomain-containing protein 4 (BRD4) is a cancer therapeutic target in ongoing clinical trials disrupting primarily BRD4-regulated transcription programs. The role of BRD4 in cancer has been attributed mainly to the abundant long isoform (BRD4-L). Here we show, by isoform-specific knockdown and endogenous protein detection, along with transgene expression, the less abundant BRD4 short isoform (BRD4-S) is oncogenic while BRD4-L is tumor-suppressive in breast cancer cell proliferation and migration, as well as mammary tumor formation and metastasis. Through integrated RNA-seq, genome-wide ChIP-seq, and CUT&RUN association profiling, we identify the Engrailed-1 (EN1) homeobox transcription factor as a key BRD4-S coregulator, particularly in triple-negative breast cancer. BRD4-S and EN1 comodulate the extracellular matrix (ECM)-associated matrisome network, including type II cystatin gene cluster, mucin 5, and cathepsin loci, via enhancer regulation of cancer-associated genes and pathways. Our work highlights the importance of targeted therapies for the oncogenic, but not tumor-suppressive, activity of BRD4.

Original languageEnglish (US)
Pages (from-to)1114-1132.e10
JournalMolecular cell
Volume78
Issue number6
DOIs
StatePublished - Jun 18 2020

Keywords

  • BET inhibitor
  • BRD4
  • CUT&RUN
  • ECM
  • TNBC
  • bromodomain
  • drug resistance
  • enhancer
  • epigenetics
  • transcription factor

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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  • Cite this

    Wu, S. Y., Lee, C. F., Lai, H. T., Yu, C. T., Lee, J. E., Zuo, H., Tsai, S. Y., Tsai, M. J., Ge, K., Wan, Y., & Chiang, C. M. (2020). Opposing Functions of BRD4 Isoforms in Breast Cancer. Molecular cell, 78(6), 1114-1132.e10. https://doi.org/10.1016/j.molcel.2020.04.034