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

Sooraj, Dhanya; Sun, Claire; Doan, Anh; Garama, Daniel J.; Dannappel, Marius; Zhu, Da‐Yuan; Chua, H.; Mahara, Sylvia; Hassan, Wan Amir Wan; Tay, Yeng Kwang; Guanizo, Aleks C.; Croagh, Daniel; Prodanovic, Zdenka; Gough, Daniel J.; Wan, Chunhua; Firestein, Ron

doi:10.1016/j.molcel.2021.11.015

Cited by 22 publications

(21 citation statements)

References 88 publications

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“…Targeting Mediator kinase function for therapeutic benefit remains a work in progress, but novel strategies continue to emerge. For example, the Firestein lab showed that bromodomain and extraterminal domain (BET) inhibitors (e.g., JQ1) may complement CDK8 + CDK19 kinase inhibition in certain cancers [109]. Moreover, compensatory increases in enhancer occupancy of MED12 and the BET protein BRD4 were observed in CDK8 + CDK19 double knockout cells (HCT116 or DLD1), suggesting functional cooperativity between the Mediator kinase module and BRD4 [109], in agreement with other studies [51,125].…”

Section: Box 2 Mediator Kinase Module and Diseasesupporting

confidence: 79%

“…Cell type and cell context (e.g., oxidative stress or growth factor induction) will remain important considerations in future work, as the set of active TFs will change in each case. Because disruption of the Mediator kinase module will broadly impact transcriptional programs [109], rapid methods to manipulate activity, such as degrons or chemical inhibitors, will be essential for delineating direct versus indirect effects. Biochemical and structural data will also continue to inform about molecular mechanisms, which are otherwise difficult to reliably assess with only cell-based or in vivo assays.…”

Section: Discussionmentioning

confidence: 99%

“…CDK8 and CDK19 have the highest sequence identity among the kinase module paralogs and inhibitors invariably block both proteins. CDK8 and CDK19 show evidence of redundant [109] and nonredundant [52] functions and each has been shown to regulate transcription in both kinase-dependent and -independent ways [25,87,109,117].…”

Section: Mediator Kinase Module Connects Cell Signaling With Transcri...mentioning

confidence: 99%

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The Mediator kinase module: an interface between cell signaling and transcription

Luyties

Taatjes

2022

Trends in Biochemical Sciences

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Section: Box 2 Mediator Kinase Module and Diseasesupporting

confidence: 79%

Section: Discussionmentioning

confidence: 99%

Section: Mediator Kinase Module Connects Cell Signaling With Transcri...mentioning

confidence: 99%

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The Mediator kinase module: an interface between cell signaling and transcription

Luyties

Taatjes

2022

Trends in Biochemical Sciences

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“…Major biological roles of the human MKM include the control of enhancer function and the regulation of transcription elongation (see the figure). Many laboratories have demonstrated that disruption of MED12 function or inhibition of Mediator kinase activity prevents normal enhancer function and disrupts activation of gene expression programmes 70 , 74 , 113 , 114 , 246 . Human MED12 may also contribute to enhancer function through binding enhancer RNA 112 and/or through regulation of CDK8 or CDK19 function 23 , 247 .…”

Section: Mediator Composition and Structurementioning

confidence: 99%

The Mediator complex as a master regulator of transcription by RNA polymerase II

Richter

Nayak

Iwasa

et al. 2022

Nat Rev Mol Cell Biol

160

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The Mediator complex, which in humans is 1.4 MDa in size and includes 26 subunits, controls many aspects of RNA polymerase II (Pol II) function. Apart from its size, a defining feature of Mediator is its intrinsic disorder and conformational flexibility, which contributes to its ability to undergo phase separation and to interact with a myriad of regulatory factors. In this Review, we discuss Mediator structure and function, with emphasis on recent cryogenic electron microscopy data of the 4.0-MDa transcription preinitiation complex. We further discuss how Mediator and sequence-specific DNA-binding transcription factors enable enhancer-dependent regulation of Pol II function at distal gene promoters, through the formation of molecular condensates (or transcription hubs) and chromatin loops. Mediator regulation of Pol II reinitiation is also discussed, in the context of transcription bursting. We propose a working model for Mediator function that combines experimental results and theoretical considerations related to enhancer–promoter interactions, which reconciles contradictory data regarding whether enhancer–promoter communication is direct or indirect. We conclude with a discussion of Mediator’s potential as a therapeutic target and of future research directions.

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“…It is currently not fully understood if cancer cells may in general be sensitive to super-enhancer deregulation, both induction and suppression, or if either one of the two is more effective, depending on the (epi)genetic background of the cancer. In addition, CDK8/19 depletion increases the activation of BRD4-bound super-enhancers by redistributing MED12 chromatin occupancy, which sensitizes cells to BET inhibition [ 66 ].…”

Section: Tm Inhibition To Target Myc and Other Super-enhancer Driven ...mentioning

confidence: 99%

Targeting the Heterogeneous Genomic Landscape in Triple-Negative Breast Cancer through Inhibitors of the Transcriptional Machinery

Noord

Water

Dévédec

2022

Cancers

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Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer defined by lack of the estrogen, progesterone and human epidermal growth factor receptor 2. Although TNBC tumors contain a wide variety of oncogenic mutations and copy number alterations, the direct targeting of these alterations has failed to substantially improve therapeutic efficacy. This efficacy is strongly limited by interpatient and intratumor heterogeneity, and thereby a lack in uniformity of targetable drivers. Most of these genetic abnormalities eventually drive specific transcriptional programs, which may be a general underlying vulnerability. Currently, there are multiple selective inhibitors, which target the transcriptional machinery through transcriptional cyclin-dependent kinases (CDKs) 7, 8, 9, 12 and 13 and bromodomain extra-terminal motif (BET) proteins, including BRD4. In this review, we discuss how inhibitors of the transcriptional machinery can effectively target genetic abnormalities in TNBC, and how these abnormalities can influence sensitivity to these inhibitors. These inhibitors target the genomic landscape in TNBC by specifically suppressing MYC-driven transcription, inducing further DNA damage, improving anti-cancer immunity, and preventing drug resistance against MAPK and PI3K-targeted therapies. Because the transcriptional machinery enables transcription and propagation of multiple cancer drivers, it may be a promising target for (combination) treatment, especially of heterogeneous malignancies, including TNBC.

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

Cited by 22 publications

References 88 publications

The Mediator kinase module: an interface between cell signaling and transcription

The Mediator kinase module: an interface between cell signaling and transcription

The Mediator complex as a master regulator of transcription by RNA polymerase II

Targeting the Heterogeneous Genomic Landscape in Triple-Negative Breast Cancer through Inhibitors of the Transcriptional Machinery

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