Stimulation of Prostate Cancer Cellular Proliferation and Invasion by the Androgen Receptor Co-Activator ARA70β

Peng, Yi; Li, Caihong X.; Chen, Fei; Wang, Zhengxin; Ligr, Martin; Melamed, Jonathan; Wei, Jian‐Jun; Gerald, William L.; Pagano, Michele; Garabedian, Michael J.; Lee, Peng

doi:10.2353/ajpath.2008.070065

Cited by 42 publications

(53 citation statements)

References 35 publications

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“…NCOA4, YWHAE, ARL6IP1 and MINA are overexpressed in a number of different cancers (Hu et al 2004, Teye et al 2004, Cimino et al 2008, Peng et al 2008, Guo et al 2010. The up-regulation of YWHAE in breast cancer is associated with diseasefree and overall survival, and therefore, the downregulation of YWHAE from reduced PRMT6 levels may be unfavourable in relation to breast cancer prognosis (Cimino et al 2008).…”

Section: Discussionmentioning

confidence: 99%

“…These genes, taken from the list of 159 differentially expressed genes, comprised six genes with decreased expression and two with increased expression following PRMT6 knockdown. The genes were chosen for their biological significance and had relevance to either steroid hormone-dependent gene expression (FK506 binding protein 4, 59 kDa: FKBP4; homeodomain interacting protein kinase 3: HIPK3 and nuclear receptor co-activator 4: NCOA4) (Yeh & Chang 1996, Moilanen et al 1998, Riggs et al 2003 and/or cancer (NCOA4, ADP-ribosylation factor-like 6 interacting protein 1: ARL6IP1; MYC-induced nuclear antigen: MINA; tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, epsilon polypeptide: YWHAE; phosphatase and tensin homolog: PTEN and insulin-like growth factor binding protein 3: IGFBP3) (Eng 2003, Hu et al 2004, Teye et al 2004, Cimino et al 2008, Peng et al 2008, Guo et al 2010, Ingermann et al 2010. PRMT6 levels were decreased in MCF-7 or T-47D breast cancer cells by siRNA for 48 h. We conducted further validation, utilising two (different) non-overlapping siRNAs targeting PRMT6 (individually) to decrease the likelihood of observing non-specific off-target effects.…”

Section: Prmt6 Influences Both Gene Activation and Repressionmentioning

confidence: 99%

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Protein arginine methyltransferase 6-dependent gene expression and splicing: association with breast cancer outcomes

Dowhan

Harrison

Eriksson

et al. 2012

Endocrine-Related Cancer

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Protein arginine methyltransferase-6 (PRMT6) regulates steroid-dependent transcription and alternative splicing and is implicated in endocrine system development and function, cell death, cell cycle, gene expression and cancer. Despite its role in these processes, little is known about its function and cellular targets in breast cancer. To identify novel gene targets regulated by PRMT6 in breast cancer cells, we used a combination of small interfering RNA and exon-specific microarray profiling in vitro coupled to in vivo validation in normal breast and primary human breast tumours. This approach, which allows the examination of genome-wide changes in individual exon usage and total transcript levels, demonstrated that PRMT6 knockdown significantly affected i) the transcription of 159 genes and ii) alternate splicing of 449 genes. The PRMT6-dependent transcriptional and alternative splicing targets identified in vitro were validated in human breast tumours. Using the list of genes differentially expressed between normal and PRMT6 knockdown cells, we generated a PRMT6-dependent gene expression signature that provides an indication of PRMT6 dysfunction in breast cancer cells. Interrogation of several well-studied breast cancer microarray expression datasets with the PRMT6 gene expression signature demonstrated that PRMT6 dysfunction is associated with better overall relapse-free and distant metastasis-free survival in the oestrogen receptor (ER (ESR1)) breast cancer subgroup. These results suggest that dysregulation of PRMT6-dependent transcription and alternative splicing may be involved in breast cancer pathophysiology and the molecular consequences identifying a unique and informative biomarker profile.

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Section: Discussionmentioning

confidence: 99%

Section: Prmt6 Influences Both Gene Activation and Repressionmentioning

confidence: 99%

Protein arginine methyltransferase 6-dependent gene expression and splicing: association with breast cancer outcomes

Dowhan

Harrison

Eriksson

et al. 2012

Endocrine-Related Cancer

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“…Indeed, we showed that ARA70␤ functions as an oncogene in promoting prostate cancer cell growth and invasion. 20 In this study, we demonstrated that ARA70␣ functions as a tumor suppressor gene in prostate cancer in in vitro and in vivo experiments.…”

mentioning

confidence: 88%

“…ARA70␤ promotes androgen-dependent growth and invasion of prostate cell lines. 20 It appears that the changes in splicing of ARA70 into its two distinct variants may be a part of such an AR-dependent mechanism, which switches between either proliferation or growth arrest and/or differentiation.…”

Section: Discussionmentioning

confidence: 99%

“…Immunoblots were blocked for 30 minutes in 3% nonfat dry milk in Trisbuffered saline Tween 20 (20 mmol/L of Tris-HCl, pH 7.6, 150 mmol/L of NaCl, and 0.1% Tween 20). Blots were incubated with antibodies raised against ARA70␣, 20 androgen receptor and ␤-actin (Sigma-Aldrich, St. Louis, MO), apoptosis-inducing factor, Bax, Bcl-XL, cleaved caspase 3, caspase 8, and p53 upregulated modulator of apoptosis (PUMA; Cell Signaling Technology, Danvers, MA) for 2 hours at room temperature, washed with Trisbuffered saline Tween 20 three times, and incubated for 1.5 hours with the secondary antibody (1:5000; Amersham Biosciences). Antibodies were diluted with 2% bovine serum albumin in Tris-buffered saline Tween 20.…”

Section: Western Blot Analysismentioning

confidence: 99%

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Tumor Suppressor Function of Androgen Receptor Coactivator ARA70α in Prostate Cancer

Ligr

Zou

et al. 2010

The American Journal of Pathology

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Androgen receptor (AR), a member of the steroid receptor family, is a transcription factor that has an important role in the regulation of both prostate cell proliferation and growth suppression. AR coactivators may influence the transition between cell growth and growth suppression. We have shown previously that the internally spliced ARA70 isoform, ARA70␤, promotes prostate cancer cell growth and invasion. Here we report that the full length ARA70␣, in contrast, represses prostate cancer cell proliferation and anchorage-independent growth in vitro and inhibits tumor growth in nude mice xenograft experiments in vivo. Further, the growth inhibition by ARA70␣ is ARdependent and mediated through induction of apoptosis rather than cell cycle arrest. Interestingly, AR with T877A mutation in LNCaP cells decreased its physical and functional interaction with ARA70␣, facilitating the growth of LNCaP cells. The tumor suppressor function of ARA70␣ is consistent with our previous findings that ARA70␣ expression is decreased in prostate cancer cells compared with benign prostate. ARA70␣ also reduced the invasion ability of LNCaP cells. Although growth inhibition by ARA70␣ is AR-dependent, the inhibition of cell invasion is an androgen-independent process. These results strongly suggest that ARA70␣ functions as a tumor suppressor gene. Androgen receptor (AR) is a transcription factor that regulates growth and differentiation of prostate cells. It mediates transcriptional activation through a series of events including ligand binding, DNA binding to androgen response elements, and interaction with various cofactors that converge on the general transcription machinery.

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Investigation of the Relationship Between Prostate Cancer andMSMBandNCOA4Genetic Variants and Protein Expression

et al. 2012

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Two genome-wide association studies (GWAS) identified the β-microseminoprotein (MSMB) promoter SNP, rs10993994:C>T, as significantly associated with prostate cancer (PC) risk. Follow-up studies demonstrate that the variant allele directly affects expression of the MSMB encoded protein, PSP94, and also suggest that it affects mRNA expression levels of an adjacent gene, NCOA4, which is involved in androgen receptor transactivation. In a population-based study of 1,323 cases and 1,268 age-matched controls, we found the NCOA4 SNP, rs7350420:T>C, was associated with a 15% reduction in PC risk, but the association was not significant after adjustment for the rs10993994:C>T genotype. Tumor tissue microarrays of 519 radical prostatectomy patients were used to measure PSP94 and NCOA4 protein expression. Taken together, these data confirm that the rs10993994:C>T variant allele is associated with decreased PSP94 expression, and the association is stronger in tumor compared to normal prostate tissue. No association was observed between rs10993994:C>T and NCOA4 expression, and only moderate associations were seen between two NCOA4 SNPs, rs10761618:T>C and rs7085433:G>A, and NCOA4 protein expression. These data indicate that the increase in PC risk associated with rs10993994:C>T is likely mediated by the variant’s effect on PSP94 expression; however this effect does not extend to NCOA4 in the data presented here.

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Stimulation of Prostate Cancer Cellular Proliferation and Invasion by the Androgen Receptor Co-Activator ARA70β

Cited by 42 publications

References 35 publications

Protein arginine methyltransferase 6-dependent gene expression and splicing: association with breast cancer outcomes

Protein arginine methyltransferase 6-dependent gene expression and splicing: association with breast cancer outcomes

Tumor Suppressor Function of Androgen Receptor Coactivator ARA70α in Prostate Cancer

Investigation of the Relationship Between Prostate Cancer andMSMBandNCOA4Genetic Variants and Protein Expression

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