Loss of MED12 Induces Tumor Dormancy in Human Epithelial Ovarian Cancer via Downregulation of EGFR

Luo, Xiao; Deng, Chang‐Mi; Su, Xiao Dong; Wang, Fang; Chen, Zhen; Wu, Xing; Liang, Shumin; Liu, Jihong; Fu, Liwu

doi:10.1158/0008-5472.can-18-0134

Cited by 24 publications

(20 citation statements)

References 41 publications

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“…The development of drug resistance requires reprogramming of signaling cascades and gene expression networks to circumvent the vulnerability exploited by the treatment [122]. The CDK8 module subunit MED12 has been implicated in multi-drug resistance in numerous cancer cell types [123,124]. In colon, lung, and other cancer cell types, its role appears to involve TGFβ signaling; specifically, under conditions of drug selection, MED12 knockdown induced TGFβR2 expression and triggered activation of MEK/ERK pathways [123].…”

Section: Cdk8 Module = Cdk8 Ccnc Med12 Med13mentioning

confidence: 99%

Regulatory functions of the Mediator kinases CDK8 and CDK19

Fant

Taatjes

2018

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The Mediator-associated kinases CDK8 and CDK19 function in the context of three additional proteins: CCNC and MED12, which activate CDK8/CDK19 kinase function, and MED13, which enables their association with the Mediator complex. The Mediator kinases affect RNA polymerase II (pol II) transcription indirectly, through phosphorylation of transcription factors and by controlling Mediator structure and function. In this review, we discuss cellular roles of the Mediator kinases and mechanisms that enable their biological functions. We focus on sequence-specific, DNA-binding transcription factors and other Mediator kinase substrates, and how CDK8 or CDK19 may enable metabolic and transcriptional reprogramming through enhancers and chromatin looping. We also summarize Mediator kinase inhibitors and their therapeutic potential. Throughout, we note conserved and divergent functions between yeast and mammalian CDK8, and highlight many aspects of kinase module function that remain enigmatic, ranging from potential roles in pol II promoter-proximal pausing to liquid-liquid phase separation.

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Section: Cdk8 Module = Cdk8 Ccnc Med12 Med13mentioning

confidence: 99%

Regulatory functions of the Mediator kinases CDK8 and CDK19

Fant

Taatjes

2018

Transcription

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“…MED12 knockout in ovarian cancer cell lines decreases EGFR protein levels. Thus, MED12 may regulate the dormancy of epithelial ovarian cancer through regulation of EGFR . In addition to the function of MED12 in genomic signaling, MED12 reportedly activated TGF‐β receptor 2 (TGF‐βR2) in the cytoplasm, constituting a nongenomic signaling pathway.…”

Section: Deregulation Of Med12 Expression In Human Cancersmentioning

confidence: 99%

“…Thus, MED12 may regulate the dormancy of epithelial ovarian cancer through regulation of EGFR. 35 In addition to the function of MED12 in genomic signaling, MED12 reportedly activated TGF-β…”

Section: Deregulation Of Med12 Expression In Human Cancersmentioning

confidence: 99%

The emerging role of mediator complex subunit 12 in tumorigenesis and response to chemotherapeutics

Zhang

O’Regan

2019

Cancer

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Transcriptional dysregulation induced by disease‐defining genetic alterations of proteins in transcriptional machinery is a key feature of cancers. Mediator complex subunit 12 (MED12) is the central architectural subunit in the kinase module of Mediator, a large transcriptional regulatory complex that controls essential steps of transcription. Emerging evidence links deregulated MED12 to human cancers. MED12 is frequently mutated in benign tumors and cancers. Although the missense mutations of MED12 in benign tumors disrupt the kinase activity of Mediator, MED12 mutations in cancers could eliminate the interaction between Mediator complex and RNA polymerase II, leading to severe transcriptional misregulation. Aberrant expression of MED12 is associated with the prognosis of various types of human cancers. Loss of MED12 function has been associated with the development of resistance to chemotherapeutics. Moreover, MED12 is modified by posttranscriptional regulations. Arginine methylation of MED12 has been shown to regulate MED12‐mediated transcriptional regulation and response to chemotherapeutics in human cancer cell lines. In this mini‐review, the authors provide an overview of the roles of MED12 in the development of benign and malignant tumors as well as its roles in chemoresistance. The studies of MED12 exemplify that aberrant transcriptional programming is a therapeutic vulnerability for certain types of cancer.

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“…Luciferase assays were performed as described in our previous reports. 21 , 22 The MHC-I promoter was purchased from GeneCopoeia Inc (Rockville, MD, USA). The 868-bp PD-L1 promoter fragment ( https://www.ncbi.nlm.nih.gov/gene/29126 ) was PCR-amplified from H460 cells genomic DNA and inserted into the promoter-less plasmid pGL3-Basic (Promega, USA) designated as p868.…”

Section: Methodsmentioning

confidence: 99%

Mitomycin C enhanced the efficacy of PD-L1 blockade in non-small cell lung cancer

Luo

Wang

Zhang

et al. 2020

Sig Transduct Target Ther

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Programmed death ligand 1 (PD-L1) immune checkpoint inhibitors are promising therapeutic agents for treating cancers but the response rate is <20%. Some chemotherapeutic drugs could also activate an anticancer immune response to kill cancer cells, apart from their direct cytotoxicity. Our study investigated the combination of chemotherapeutic drugs with PD-L1 antibody to enhance the response rate of PD-L1 blockade. Non-small cell lung cancer (NSCLC) cells were pre-treated with mitomycin C (MMC) and then co-cultured with peripheral blood mononuclear cells (PBMCs) to investigate the effect of the combination of MMC with PD-L1 antibody. The drug combination was also evaluated in vivo in Lewis lung cancer (LLC) cells-bearing C57BL/6 mice. MMC increased the expressions of PD-L1 and MHC-I in NSCLC cells in vitro and in vivo and enhanced the cytotoxic effect of lymphocytes on NSCLC in vitro. In LLC-bearing mouse model, the combination of MMC and PD-L1 antibody was found to be more effective in retarding tumor growth and prolonging overall survival than either single treatment alone, which was associated with increased lymphocyte infiltration and granzyme B release. Mechanistically, MMC activated the ERK pathway, which subsequently enhanced the binding of c-JUN to the PD-L1 promoter and recruited its co-factor STAT3 to increase PD-L1 expression. The upregulated ERK pathway was shown to activate p65 to increase the MHC-I expression. MMC was shown to enhance the efficacy of PD-L1 blockade in NSCLC cells. Further study is warranted to translate the findings to clinical application.

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Loss of MED12 Induces Tumor Dormancy in Human Epithelial Ovarian Cancer via Downregulation of EGFR

Cited by 24 publications

References 41 publications

Regulatory functions of the Mediator kinases CDK8 and CDK19

Regulatory functions of the Mediator kinases CDK8 and CDK19

The emerging role of mediator complex subunit 12 in tumorigenesis and response to chemotherapeutics

Mitomycin C enhanced the efficacy of PD-L1 blockade in non-small cell lung cancer

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