Protein arginine methyltransferase 5 functions as an epigenetic activator of the androgen receptor to promote prostate cancer cell growth

Deng, Xiangbing; Shao, Gang; Ht, Zhang; C, Li; Zhang, Danting; Cheng, Liang; Bd, Elzey; Пили, Роберто; Tl, Ratliff; Huang, Jiaoti; Hu, C. D.

doi:10.1038/onc.2016.287

Cited by 125 publications

(145 citation statements)

References 49 publications

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“…The BTG2 protein increase induced by PRMT5 inhibition was blocked when cells were pretreated with an ERK inhibitor (PD0325901). In addition, Chen et al [27] reported that PRMT5 activity was necessary for its phenotypes. To provide additional evidence for this hypothesis, we used GSK591 to block PRMT5 activity.…”

Section: Discussionmentioning

confidence: 99%

PRMT5 promotes cell proliferation by inhibiting BTG2 expression via the ERK signaling pathway in hepatocellular carcinoma

et al. 2018

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Increasing evidence suggests that PRMT5, a protein arginine methyltransferase, has roles in cell growth regulation and cancer development. However, the role of PRMT5 in hepatocellular carcinoma (HCC) progression remains unclear. Here, we showed that PRMT5 expression was frequently upregulated in HCC tissues, and its expression was inversely correlated with overall survival in HCC patients. PRMT5 knockdown markedly inhibited in vitro HCC proliferation and in vivo tumorigenesis. We revealed that the mechanism of PRMT5‐induced proliferation was partially mediated by BTG downregulation, leading to cell cycle arrest during the G1 phase in HCC cells. Ectopic BTG2 overexpression decreased HCC growth, caused cell cycle arrest at the G1 phase, and downregulated Cyclin D1 and Cyclin E1 protein expression. Furthermore, we found that PRMT5‐induced ERK phosphorylation regulated BTG2 expression in HCC cells, whereas pretreatment with a selective ERK1/2 inhibitor (PD184352) significantly reversed the effect of PRMT5 on BTG2 expression. Our results indicated that PRMT5 promotes HCC proliferation by downregulating BTG2 expression via the ERK pathway.

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Section: Discussionmentioning

confidence: 99%

PRMT5 promotes cell proliferation by inhibiting BTG2 expression via the ERK signaling pathway in hepatocellular carcinoma

et al. 2018

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“…Mechanistically, Sp1 can interact directly with the transcriptional machinery (TFIID) to initiate transcription. However, more recently Sp1 was found to recruit the chromatin modifying enzymes Brg1 and protein arginine methyltransferase, PRMT 5, to the AR promoter (Deng et al 2017). This epigenetic regulation was correlated with increased AR expression and prostate cancer cell growth.…”

Section: Role Of Transcription Factor Sp1mentioning

confidence: 99%

Tissue control of androgen action: The ups and downs of androgen receptor expression

Hunter

Hay

Esswein

et al. 2018

Molecular and Cellular Endocrinology

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Please cite this article as: Hunter, I., Hay, C.W., Esswein, B., Watt, K., McEwan, I.J., Tissue control of androgen action: The ups and downs of androgen receptor expression, Molecular and Cellular Endocrinology (2017), doi: 10.1016/j.mce.2017 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…In particular, PRMT5-mediated posttranslational histone modification significantly affects gene expression and ultimately induces abnormal cell growth and proliferation (38,39). Overexpression or dysregulation of PRMT5 has been reported in a number of cancers, including ovarian, breast, lung, lymphoid, lymphoma, melanoma, colon, gastric, prostate, and bladder cancer and germ cell tumors (13,40,41). Negative regulation of histone arginine methylation by M6CK raises the possibility that TRPM6 could be used as an endogenous PRMT5 inhibitor to suppress some tumors.…”

Section: Discussionmentioning

confidence: 99%

Histone phosphorylation by TRPM6’s cleaved kinase attenuates adjacent arginine methylation to regulate gene expression

Krapivinsky

Renthal

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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TRPM6 and TRPM7 are members of the melastatin-related transient receptor potential (TRPM) subfamily of ion channels. Deletion of either gene in mice is embryonically lethal. TRPM6/7 are the only known examples of single polypeptides containing both an ion channel pore and a serine/threonine kinase (chanzyme). Here we show that the C-terminal kinase domain of TRPM6 is cleaved from the channel domain in a cell type-specific fashion and is active. Cleavage requires that the channel conductance is functional. The cleaved kinase translocates to the nucleus, where it is strictly localized and phosphorylates specific histone serine and threonine (S/T) residues. TRPM6-cleaved kinases (M6CKs) bind subunits of the protein arginine methyltransferase 5 (PRMT5) molecular complex that make important epigenetic modifications by methylating histone arginine residues. Histone phosphorylation by M6CK results in a dramatic decrease in methylation of arginines adjacent to M6CK-phosphorylated amino acids. Knockout of TRPM6 or inactivation of its kinase results in global changes in histone S/T phosphorylation and changes the transcription of hundreds of genes. We hypothesize that M6CK associates with the PRMT5 molecular complex in the nucleus, directing M6CK to a specific genomic location and providing site-specific histone phosphorylation. M6CK histone phosphorylation, in turn, regulates transcription by attenuating the effect of local arginine methylation.A mong the several hundred genes encoding cation channels, the melastatin-related transient receptor potential family members TRPM6 and TRPM7 are unique in also being serine/ threonine (S/T) kinases (1). The TRPM6 channel kinase was brought to greater attention when mutations in this chanzyme were found to be the cause of familial hypomagnesemia with secondary hypocalcemia (HSH; see ref. 2 for a recent review). Characterized by severe hypomagnesemia, infants with HSH suffer tetany and refractory seizures shortly after birth, resulting in permanent neurological damage or death if untreated. The mechanisms by which mutations in TRPM6 lead to HSH are unknown, although several studies stress the importance of TRPM6-mediated Mg 2+ conductance (3-5). Importantly, global TRPM6 disruption in mice is embryonic lethal (6, 7). Mice with loss of TRPM6 at intermediate developmental time points manifest a reduced life span and skeletal deformations, in addition to mild hypomagnesemia (5). These data indicate that, much like TRPM7 (8), TRPM6 may be critical for normal, developmental, tissue-specific regulation of gene activity.Recently, our laboratory uncovered a signaling pathway mediated by TRPM7, a channel sharing 52% homology with TRPM6, whereby the functional S/T kinase at the carboxyl terminus of TRPM7 is proteolytically cleaved from the channel domain, forming cleaved kinase fragments (M7CKs) that translocate to the nucleus (9). There, M7CKs bind components of chromatin-remodeling complexes to ultimately phosphorylate specific S/T residues of histones, regulate selected histone acetylatio...

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Protein arginine methyltransferase 5 functions as an epigenetic activator of the androgen receptor to promote prostate cancer cell growth

Cited by 125 publications

References 49 publications

PRMT5 promotes cell proliferation by inhibiting BTG2 expression via the ERK signaling pathway in hepatocellular carcinoma

PRMT5 promotes cell proliferation by inhibiting BTG2 expression via the ERK signaling pathway in hepatocellular carcinoma

Tissue control of androgen action: The ups and downs of androgen receptor expression

Histone phosphorylation by TRPM6’s cleaved kinase attenuates adjacent arginine methylation to regulate gene expression

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