Roles of the androgen receptor cofactor p44 in the growth of prostate epithelial cells

Zhou, Liran; Wu, Hong; Lee, Peng; Wang, Zhengxin

doi:10.1677/jme.1.02062

Cited by 34 publications

(108 citation statements)

References 46 publications

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“…In adult prostate, p44 is expressed as nuclear protein in glandular epithelial cells and not in stromal cells (Zhou et al, 2006). In testis, p44 expression is seen in germ cells and Leydig cells, but not expressed in peritubular myocytes and Sertoli's cells (Liang et al, 2006).…”

Section: Expressionmentioning

confidence: 99%

“…p44 has both nuclear and cytolasmic localization patterns (Zhou et al, 2006;Liang et al, 2006;Peng et al, 2008). In benign prostate and testicular cells, p44 is found predominantly in the nucleus.…”

Section: Localisationmentioning

confidence: 99%

“…Nuclear p44 causes an androgen-dependent G1 arrest growth inhibition in prostate cells expressing androgen receptor (Zhou et al, 2006;Peng et al, 2008). Cytoplasmic and nuclear p44 may have opposite functions, as introduction of p44 to the cytoplasm accelerates growth (Peng et al, 2008).…”

Section: Functionmentioning

confidence: 99%

Section: Diseasementioning

confidence: 99%

“…2009;13(10) 667 localization in benign tissue (Zhou et al, 2006). Translocation from the nucleus in benign cells to the cytoplasm is strongly associated with prostate tumorigenesis (Zhou et al, 2006;Peng et al, 2008). Cytoplasmic expressed p44 also leads to increased growth in androgen dependent prostate cell line LNCaP (Peng et al, 2008).…”

Section: Diseasementioning

confidence: 99%

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WDR77 (WD repeat domain 77)

Daniels¹,

Wang²,

Lee³

2011

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Section: Expressionmentioning

confidence: 99%

Section: Localisationmentioning

confidence: 99%

Section: Functionmentioning

confidence: 99%

Section: Diseasementioning

confidence: 99%

Section: Diseasementioning

confidence: 99%

See 3 more Smart Citations

WDR77 (WD repeat domain 77)

Daniels¹,

Wang²,

Lee³

2011

Atlas of Genetics and Cytogenetics in Oncology and Haematology

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Protein arginine methyltransferase 5: A novel therapeutic target for triple‐negative breast cancers

et al. 2019

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TNBC is a highly heterogeneous and aggressive breast cancer subtype associated with high relapse rates, and for which no targeted therapy yet exists. Protein arginine methyltransferase 5 (PRMT5), an enzyme which catalyzes the methylation of arginines on histone and non‐histone proteins, has recently emerged as a putative target for cancer therapy. Potent and specific PRMT5 inhibitors have been developed, but the therapeutic efficacy of PRMT5 targeting in TNBC has not yet been demonstrated. Here, we examine the expression of PRMT5 in a human breast cancer cohort obtained from the Institut Curie, and evaluate the therapeutic potential of pharmacological inhibition of PRMT5 in TNBC. We find that PRMT5 mRNA and protein are expressed at comparable levels in TNBC, luminal breast tumors, and healthy mammary tissues. However, immunohistochemistry analyses reveal that PRMT5 is differentially localized in TNBC compared to other breast cancer subtypes and to normal breast tissues. PRMT5 is heterogeneously expressed in TNBC and high PRMT5 expression correlates with poor prognosis within this breast cancer subtype. Using the small‐molecule inhibitor EPZ015666, we show that PRMT5 inhibition impairs cell proliferation in a subset of TNBC cell lines. PRMT5 inhibition triggers apoptosis, regulates cell cycle progression and decreases mammosphere formation. Furthermore, EPZ015666 administration to a patient‐derived xenograft model of TNBC significantly deters tumor progression. Finally, we reveal potentiation between EGFR and PRMT5 targeting, suggestive of a beneficial combination therapy. Our findings highlight a distinctive subcellular localization of PRMT5 in TNBC, and uphold PRMT5 targeting, alone or in combination, as a relevant treatment strategy for a subset of TNBC.

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The PRMT5 arginine methyltransferase: many roles in development, cancer and beyond

Stopa

Krebs

Shechter

2015

Cell. Mol. Life Sci.

405

399

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Post-translational arginine methylation is responsible for regulation of many biological processes. The protein arginine methyltransferase 5 (PRMT5, also known as Hsl7, Jbp1, Skb1, Capsuleen, or Dart5) is the major enzyme responsible for mono- and symmetric dimethylation of arginine. An expanding literature demonstrates its critical biological function in a wide range of cellular processes. Histone and other protein methylation by PRMT5 regulate genome organization, transcription, stem cells, primordial germ cells, differentiation, the cell cycle, and spliceosome assembly. Metazoan PRMT5 is found in complex with the WD-repeat protein MEP50 (also known as Wdr77, androgen receptor coactivator p44, or Valois). PRMT5 also directly associates with a range of other protein factors, including pICln, Menin, CoPR5 and RioK1 that may alter its subcellular localization and protein substrate selection. Protein substrate and PRMT5–MEP50 post-translation modifications induce crosstalk to regulate PRMT5 activity. Crystal structures of C. elegans PRMT5 and human and frog PRMT5–MEP50 complexes provide substantial insight into the mechanisms of substrate recognition and procession to dimethylation. Enzymo-logical studies of PRMT5 have uncovered compelling insights essential for future development of specific PRMT5 inhibitors. In addition, newly accumulating evidence implicates PRMT5 and MEP50 expression levels and their methyltransferase activity in cancer tumorigenesis, and, significantly, as markers of poor clinical outcome, marking them as potential oncogenes. Here, we review the substantial new literature on PRMT5 and its partners to highlight the significance of understanding this essential enzyme in health and disease.

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Roles of the androgen receptor cofactor p44 in the growth of prostate epithelial cells

Cited by 34 publications

References 46 publications

WDR77 (WD repeat domain 77)

WDR77 (WD repeat domain 77)

Protein arginine methyltransferase 5: A novel therapeutic target for triple‐negative breast cancers

The PRMT5 arginine methyltransferase: many roles in development, cancer and beyond

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