JMJD6 Licenses ERα-Dependent Enhancer and Coding Gene Activation by Modulating the Recruitment of the CARM1/MED12 Co-activator Complex

Gao, Weiwei; Xiao, Rong-quan; Zhang, Wen-juan; Hu, Yiren; Peng, Bing‐ling; Li, Wenjuan; He, Yaohui; Shen, Hai‐feng; Ding, Jian; Huang, Qi-xuan; Ye, Tian-yi; Liu, Ying; Liu, Zhiying; Ding, Rong; Rosenfeld, Michael G.; Li, Wen

doi:10.1016/j.molcel.2018.03.006

Cited by 76 publications

(103 citation statements)

References 94 publications

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“…This is in accordance with results by Sharma et al (2017) who identified the gene network modules including CARM1 and ER signalling modules associated with metastasis and the progression of the disease (Sharma et al 2017). Furthermore, JmjC domain containing protein 6 (JMJD6) drives the interaction with the MED12 mediator complex that interacts with CARM1 and is involved in ERαdependent breast cancer cellular proliferation (Gao et al 2018). Hiken et al (2017) demonstrated that aromatise inhibitor endocrine-resistant breast cancer is associated with increased prostaglandin E 2 receptor 4 (PTGER4) expression, a protein that drives agonist-independent activity of CARM1 (Hiken et al 2017).…”

Section: Protein Arginine Methyltransferasesupporting

confidence: 90%

Epigenetic arginine methylation in breast cancer: emerging therapeutic strategies

Wang

Dowhan

Muscat

2019

Journal of Molecular Endocrinology

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Breast cancer is a heterogeneous disease, and the complexity of breast carcinogenesis is associated with epigenetic modification. There are several major classes of epigenetic enzymes that regulate chromatin activity. This review will focus on the nine mammalian protein arginine methyltransferases (PRMTs) and the dysregulation of PRMT expression and function in breast cancer. This class of enzymes catalyse the mono- and (symmetric and asymmetric) di-methylation of arginine residues on histone and non-histone target proteins. PRMT signalling (and R methylation) drives cellular proliferation, cell invasion and metastasis, targeting (i) nuclear hormone receptor signalling, (ii) tumour suppressors, (iii) TGF-β and EMT signalling and (iv) alternative splicing and DNA/chromatin stability, influencing the clinical and survival outcomes in breast cancer. Emerging reports suggest that PRMTs are also implicated in the development of drug/endocrine resistance providing another prospective avenue for the treatment of hormone resistance and associated metastasis. The complexity of PRMT signalling is further underscored by the degree of alternative splicing and the scope of variant isoforms (with distinct properties) within each PRMT family member. The evolution of PRMT inhibitors, and the ongoing clinical trials of PRMT inhibitors against a subgroup of solid cancers, coupled to the track record of lysine methyltransferases inhibitors in phase I/II clinical trials against cancer underscores the potential therapeutic utility of targeting PRMT epigenetic enzymes to improve survival outcomes in aggressive and metastatic breast cancer.

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Section: Protein Arginine Methyltransferasesupporting

confidence: 90%

Epigenetic arginine methylation in breast cancer: emerging therapeutic strategies

Wang

Dowhan

Muscat

2019

Journal of Molecular Endocrinology

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“…JMJD6 is a multifunctional protein: it is an iron (Fe2+) and 2‐oxoglutarate (2‐OG)–dependent dioxygenase as well as a protein arginine demethylase. Because JMJD6 plays an essential role in ER transcription and can hydroxylate lysines on both histones and nonhistone proteins, it may be exploited as a molecular target for developing epigenetic therapies for ERα‐positive breast cancers . Although MED12 functionally regulates ERα signaling, mutations of MED12 were more common in triple‐negative breast cancer than in ERα‐positive breast cancer, indicating that MED12 might play different roles in triple‐negative‐dependent and estrogen‐dependent breast cancers, as in the cases of lung cancers.…”

Section: The Relevance Of Med12 To the Estrogen Pathwaymentioning

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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“…Mediator complex subunit 12 (MED12) is involved in transcriptional regulation of a variety of signalling pathways, including oestrogen‐induced transcriptional activation . Mechanistically, JMJD6 specifically interacts with C‐terminus of MED12 and regulates its recruitment to ERα‐bound active enhancers, thereby affecting oestrogen‐induced transcriptional activation . Furthermore, JMJD6 is required for MED12 interaction with CARM1 (co‐activator associated arginine methyltransferase 1) .…”

Section: Mechanisms Of Jmjd6 In Promoting Cancer Developmentmentioning

confidence: 99%

Jumonji domain‐containing protein 6 protein and its role in cancer

et al. 2020

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The jumonji domain‐containing protein 6 (JMJD6) is a Fe(II)‐ and 2‐oxoglutarate (2OG)‐dependent oxygenase that catalyses lysine hydroxylation and arginine demethylation of histone and non‐histone peptides. Recently, the intrinsic tyrosine kinase activity of JMJD6 has also been reported. The JMJD6 has been implicated in embryonic development, cellular proliferation and migration, self‐tolerance induction in the thymus, and adipocyte differentiation. Not surprisingly, abnormal expression of JMJD6 may contribute to the development of many diseases, such as neuropathic pain, foot‐and‐mouth disease, gestational diabetes mellitus, hepatitis C and various types of cancer. In the present review, we summarized the structure and functions of JMJD6, with particular emphasis on the role of JMJD6 in cancer progression.

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JMJD6 Licenses ERα-Dependent Enhancer and Coding Gene Activation by Modulating the Recruitment of the CARM1/MED12 Co-activator Complex

Cited by 76 publications

References 94 publications

Epigenetic arginine methylation in breast cancer: emerging therapeutic strategies

Epigenetic arginine methylation in breast cancer: emerging therapeutic strategies

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

Jumonji domain‐containing protein 6 protein and its role in cancer

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