MED12 and BRD4 cooperate to sustain cancer growth upon loss of mediator kinase

Dhanya Sooraj, Claire Sun, Anh Doan, Daniel J. Garama, Marius V. Dannappel, Danxi Zhu, Hui K. Chua, Sylvia Mahara, Wan Amir Wan Hassan, Yeng Kwang Tay, Aleks Guanizo, Daniel Croagh, Zdenka Prodanovic, Daniel J. Gough, Chunhua Wan, Ron Firestein

Research output: Contribution to journalArticleResearchpeer-review

3 Citations (Scopus)

Abstract

Mediator kinases (CDK8/19) are transcriptional regulators broadly implicated in cancer. Despite their central role in fine-tuning gene-expression programs, we find complete loss of CDK8/19 is tolerated in colorectal cancer (CRC) cells. Using orthogonal functional genomic and pharmacological screens, we identify BET protein inhibition as a distinct vulnerability in CDK8/19-depleted cells. Combined CDK8/19 and BET inhibition led to synergistic growth retardation in human and mouse models of CRC. Strikingly, depletion of CDK8/19 in these cells led to global repression of RNA polymerase II (Pol II) promoter occupancy and transcription. Concurrently, loss of Mediator kinase led to a profound increase in MED12 and BRD4 co-occupancy at enhancer elements and increased dependence on BET proteins for the transcriptional output of cell-essential genes. In total, this work demonstrates a synthetic lethal interaction between Mediator kinase and BET proteins and exposes a therapeutic vulnerability that can be targeted using combination therapies.

Original languageEnglish
Pages (from-to)123-139.e7
Number of pages25
JournalMolecular Cell
Volume82
Issue number1
DOIs
Publication statusPublished - 6 Jan 2022

Keywords

  • BRD4
  • cancer
  • CDK8
  • chromatin
  • combination therapy
  • enhancer
  • Mediator complex
  • precision medicine
  • synthetic lethality
  • transcription

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