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

doi:10.1016/j.molcel.2021.11.015

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 journal › Article › Research › peer-review

22 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 language	English
Pages (from-to)	123-139.e7
Number of pages	25
Journal	Molecular Cell
Volume	82
Issue number	1
DOIs	https://doi.org/10.1016/j.molcel.2021.11.015
Publication status	Published - 6 Jan 2022

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.molcel.2021.11.015

Cite this

Sooraj, D., Sun, C., Doan, A., Garama, D. J., Dannappel, M. V., Zhu, D., Chua, H. K., Mahara, S., Wan Hassan, W. A., Tay, Y. K., Guanizo, A., Croagh, D., Prodanovic, Z., Gough, D. J., Wan, C., & Firestein, R. (2022). MED12 and BRD4 cooperate to sustain cancer growth upon loss of mediator kinase. Molecular Cell, 82(1), 123-139.e7. https://doi.org/10.1016/j.molcel.2021.11.015

@article{ad77c0d221774a018639ec4099640537,

title = "MED12 and BRD4 cooperate to sustain cancer growth upon loss of mediator kinase",

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, cancer, CDK8, chromatin, combination therapy, enhancer, Mediator complex, precision medicine, synthetic lethality, transcription",

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

note = "Funding Information: We thank Drs. Helen Abud and Genevieive Kerr (Monash University) for organoid reagents; Mr. Lin, Dr. Pouya Faridi, Dr. Labhart, and Dr. Mark Condina (Mass Dynamics) for technical assistance; the Melbourne Mass Spectrometry and Proteomics Facility at The Bio21 Institute; and Dr. Bryan Williams, Ms. Stephanie Forman, and Mr. Bob Doyle for administrative support. Cortistatin A was provided by Dr. Matthew Shair, Department of Chemistry, Harvard University. Funding support from the National Health and Medical Research Council (NHMRC), Australia grants APP1129689 and APP1144969. D.S. C.S. and R.F. conceived the study, designed and performed the experiments, analyzed the data, and wrote the manuscript. A.D. A.G. C.W. D.J. Garama, D.J. Gough, M.V.D. D.Z. H.K.C. and S.M. performed experiments and analyzed data. W.A.W.H. and Z.P. collected and established organoid protocols. All authors discussed the results and reviewed the manuscript. The authors declare no competing interests. Funding Information: We thank Drs. Helen Abud and Genevieive Kerr (Monash University) for organoid reagents; Mr. Lin, Dr. Pouya Faridi, Dr. Labhart, and Dr. Mark Condina (Mass Dynamics) for technical assistance; the Melbourne Mass Spectrometry and Proteomics Facility at The Bio21 Institute; and Dr. Bryan Williams, Ms. Stephanie Forman, and Mr. Bob Doyle for administrative support. Cortistatin A was provided by Dr. Matthew Shair, Department of Chemistry, Harvard University. Funding support from the National Health and Medical Research Council (NHMRC), Australia grants APP1129689 and APP1144969 . Publisher Copyright: {\textcopyright} 2021 Elsevier Inc.",

year = "2022",

month = jan,

day = "6",

doi = "10.1016/j.molcel.2021.11.015",

language = "English",

volume = "82",

pages = "123--139.e7",

journal = "Molecular Cell",

issn = "1097-2765",

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number = "1",

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TY - JOUR

T1 - MED12 and BRD4 cooperate to sustain cancer growth upon loss of mediator kinase

AU - Sooraj, Dhanya

AU - Sun, Claire

AU - Doan, Anh

AU - Garama, Daniel J.

AU - Dannappel, Marius V.

AU - Zhu, Danxi

AU - Chua, Hui K.

AU - Mahara, Sylvia

AU - Wan Hassan, Wan Amir

AU - Tay, Yeng Kwang

AU - Guanizo, Aleks

AU - Croagh, Daniel

AU - Prodanovic, Zdenka

AU - Gough, Daniel J.

AU - Wan, Chunhua

AU - Firestein, Ron

N1 - Funding Information: We thank Drs. Helen Abud and Genevieive Kerr (Monash University) for organoid reagents; Mr. Lin, Dr. Pouya Faridi, Dr. Labhart, and Dr. Mark Condina (Mass Dynamics) for technical assistance; the Melbourne Mass Spectrometry and Proteomics Facility at The Bio21 Institute; and Dr. Bryan Williams, Ms. Stephanie Forman, and Mr. Bob Doyle for administrative support. Cortistatin A was provided by Dr. Matthew Shair, Department of Chemistry, Harvard University. Funding support from the National Health and Medical Research Council (NHMRC), Australia grants APP1129689 and APP1144969. D.S. C.S. and R.F. conceived the study, designed and performed the experiments, analyzed the data, and wrote the manuscript. A.D. A.G. C.W. D.J. Garama, D.J. Gough, M.V.D. D.Z. H.K.C. and S.M. performed experiments and analyzed data. W.A.W.H. and Z.P. collected and established organoid protocols. All authors discussed the results and reviewed the manuscript. The authors declare no competing interests. Funding Information: We thank Drs. Helen Abud and Genevieive Kerr (Monash University) for organoid reagents; Mr. Lin, Dr. Pouya Faridi, Dr. Labhart, and Dr. Mark Condina (Mass Dynamics) for technical assistance; the Melbourne Mass Spectrometry and Proteomics Facility at The Bio21 Institute; and Dr. Bryan Williams, Ms. Stephanie Forman, and Mr. Bob Doyle for administrative support. Cortistatin A was provided by Dr. Matthew Shair, Department of Chemistry, Harvard University. Funding support from the National Health and Medical Research Council (NHMRC), Australia grants APP1129689 and APP1144969 . Publisher Copyright: © 2021 Elsevier Inc.

PY - 2022/1/6

Y1 - 2022/1/6

N2 - 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.

AB - 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.

KW - BRD4

KW - cancer

KW - CDK8

KW - chromatin

KW - combination therapy

KW - enhancer

KW - Mediator complex

KW - precision medicine

KW - synthetic lethality

KW - transcription

UR - https://www.scopus.com/pages/publications/85121910745

U2 - 10.1016/j.molcel.2021.11.015

DO - 10.1016/j.molcel.2021.11.015

M3 - Article

C2 - 34910943

AN - SCOPUS:85121910745

SN - 1097-2765

VL - 82

SP - 123-139.e7

JO - Molecular Cell

JF - Molecular Cell

IS - 1

ER -

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

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Therapeutic targeting of the colorectal epigenome

Mediator kinase as a therapeutic target for Wnt/B-catenin dependent malignancies

Cite this

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

Abstract

Keywords

UN SDGs

Access to Document

Other files and links

Projects

Therapeutic targeting of the colorectal epigenome

Mediator kinase as a therapeutic target for Wnt/B-catenin dependent malignancies

Cite this