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

Mol Cell. 2022 Jan 6;82(1):123-139.e7. doi: 10.1016/j.molcel.2021.11.015. Epub 2021 Dec 14.

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.

Keywords: BRD4; CDK8; Mediator complex; cancer; chromatin; combination therapy; enhancer; precision medicine; synthetic lethality; transcription.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use
  • Binding Sites
  • Cell Cycle Proteins / antagonists & inhibitors
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Proliferation* / drug effects
  • Colorectal Neoplasms / drug therapy
  • Colorectal Neoplasms / enzymology*
  • Colorectal Neoplasms / genetics
  • Cyclin-Dependent Kinase 8 / genetics
  • Cyclin-Dependent Kinase 8 / metabolism*
  • Cyclin-Dependent Kinases / genetics
  • Cyclin-Dependent Kinases / metabolism*
  • Enhancer Elements, Genetic
  • Female
  • Gene Expression Regulation, Neoplastic
  • HCT116 Cells
  • Humans
  • Male
  • Mediator Complex / antagonists & inhibitors
  • Mediator Complex / genetics
  • Mediator Complex / metabolism*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Knockout
  • Mice, Nude
  • Nerve Tissue Proteins / antagonists & inhibitors
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Nuclear Proteins / antagonists & inhibitors
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Protein Kinase Inhibitors / pharmacology
  • Receptors, Cell Surface / antagonists & inhibitors
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism
  • Signal Transduction
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • Tumor Burden
  • Xenograft Model Antitumor Assays

Substances

  • BRD4 protein, human
  • Brd4 protein, mouse
  • Cell Cycle Proteins
  • DNER protein, human
  • MED12 protein, human
  • Med12 protein, mouse
  • Mediator Complex
  • Nerve Tissue Proteins
  • Nuclear Proteins
  • Protein Kinase Inhibitors
  • Receptors, Cell Surface
  • Transcription Factors
  • CDK19 protein, human
  • CDK19 protein, mouse
  • CDK8 protein, human
  • Cdk8 protein, mouse
  • Cyclin-Dependent Kinase 8
  • Cyclin-Dependent Kinases