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Poly (A) Binding Protein Cytoplasmic 1 Is a Novel Co-Regulator of the Androgen Receptor.

Eisermann K, Dar JA, Dong J, Wang D, Masoodi KZ, Wang Z - PLoS ONE (2015)

Bottom Line: Mass spectrometry analysis of the pulled down proteins identified poly (A) binding protein cytoplasmic 1 (PABPC1) interaction with this region of the AR.Knockdown of PABPC1 decreased nuclear AR protein levels and inhibited androgen activation of the AR target PSA in LNCaP and C4-2 cells.These findings suggest that PABPC1 is a novel co-regulator of the AR and may be a potential target for blocking activation of the AR in CRPC.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.

ABSTRACT
The androgen receptor (AR) is a member of the steroid receptor superfamily that regulates gene expression in a ligand-dependent manner. The NTD of the AR plays a key role in AR transactivation including androgen-independent activation of the AR in castration-resistant prostate cancer (CRPC) cells. We recently reported that amino acids (a.a.) 50-250 of the NTD are capable of modulating AR nucleocytoplasmic trafficking. To further explore the mechanism associated with a.a. 50-250, GFP pull-down assays were performed in C4-2 CRPC cells transfected with GFP tagged a.a. 50-250 of the AR. Mass spectrometry analysis of the pulled down proteins identified poly (A) binding protein cytoplasmic 1 (PABPC1) interaction with this region of the AR. In silico analysis of gene expression data revealed PABPC1 up-regulation in prostate cancer tissue specimens and this up-regulation correlates to increased disease recurrence. Co-immunoprecipitation assays confirmed the association of PABPC1 with a.a. 50-250 of the NTD of the AR. Knockdown of PABPC1 decreased nuclear AR protein levels and inhibited androgen activation of the AR target PSA in LNCaP and C4-2 cells. Additionally, knockdown of PABPC1 inhibited transactivation of the PSA promoter by NAR (AR lacking the LBD) and attenuated proliferation of AR-positive prostate cancer cells. These findings suggest that PABPC1 is a novel co-regulator of the AR and may be a potential target for blocking activation of the AR in CRPC.

No MeSH data available.


Related in: MedlinePlus

Up-regulation of PABPC1 correlates with increased disease recurrence.In silico analysis of the MSKCC cBioPortal for Cancer Genomics database for prostate adenocarcinoma was performed for PABPC1. Kaplan Meier plot of the risk of disease recurrence for patients with up-regulation in PABPC1 compared to patients without any alterations in PABPC1 is shown (23, 24).
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pone.0128495.g001: Up-regulation of PABPC1 correlates with increased disease recurrence.In silico analysis of the MSKCC cBioPortal for Cancer Genomics database for prostate adenocarcinoma was performed for PABPC1. Kaplan Meier plot of the risk of disease recurrence for patients with up-regulation in PABPC1 compared to patients without any alterations in PABPC1 is shown (23, 24).

Mentions: To explore the expression of PABPC1 in prostate tumors, in silico analysis was performed using Oncomine [18]. Multiple studies [19–22] showed that PABPC1 was up-regulated in prostate cancer specimens compared with normal controls (Table 1). Additionally, analysis of the MSKCC cBioPortal for Cancer Genomics database showed that PABPC1 was up-regulated in 44 of 216 (20%) tumor samples [23–25]. In the MSKCC cohort, patients with up-regulation of PABPC1 were shown to have increased disease recurrence (Fig 1). Up-regulation of PABPC1 significantly shortened the time to disease recurrence to only 64 months disease free with up-regulated PABPC1 from 110 months disease free without increased expression of PABPC1 (Fig 1). This suggests a significant role for PABPC1 in prostate carcinogenesis.


Poly (A) Binding Protein Cytoplasmic 1 Is a Novel Co-Regulator of the Androgen Receptor.

Eisermann K, Dar JA, Dong J, Wang D, Masoodi KZ, Wang Z - PLoS ONE (2015)

Up-regulation of PABPC1 correlates with increased disease recurrence.In silico analysis of the MSKCC cBioPortal for Cancer Genomics database for prostate adenocarcinoma was performed for PABPC1. Kaplan Meier plot of the risk of disease recurrence for patients with up-regulation in PABPC1 compared to patients without any alterations in PABPC1 is shown (23, 24).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4503479&req=5

pone.0128495.g001: Up-regulation of PABPC1 correlates with increased disease recurrence.In silico analysis of the MSKCC cBioPortal for Cancer Genomics database for prostate adenocarcinoma was performed for PABPC1. Kaplan Meier plot of the risk of disease recurrence for patients with up-regulation in PABPC1 compared to patients without any alterations in PABPC1 is shown (23, 24).
Mentions: To explore the expression of PABPC1 in prostate tumors, in silico analysis was performed using Oncomine [18]. Multiple studies [19–22] showed that PABPC1 was up-regulated in prostate cancer specimens compared with normal controls (Table 1). Additionally, analysis of the MSKCC cBioPortal for Cancer Genomics database showed that PABPC1 was up-regulated in 44 of 216 (20%) tumor samples [23–25]. In the MSKCC cohort, patients with up-regulation of PABPC1 were shown to have increased disease recurrence (Fig 1). Up-regulation of PABPC1 significantly shortened the time to disease recurrence to only 64 months disease free with up-regulated PABPC1 from 110 months disease free without increased expression of PABPC1 (Fig 1). This suggests a significant role for PABPC1 in prostate carcinogenesis.

Bottom Line: Mass spectrometry analysis of the pulled down proteins identified poly (A) binding protein cytoplasmic 1 (PABPC1) interaction with this region of the AR.Knockdown of PABPC1 decreased nuclear AR protein levels and inhibited androgen activation of the AR target PSA in LNCaP and C4-2 cells.These findings suggest that PABPC1 is a novel co-regulator of the AR and may be a potential target for blocking activation of the AR in CRPC.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, United States of America.

ABSTRACT
The androgen receptor (AR) is a member of the steroid receptor superfamily that regulates gene expression in a ligand-dependent manner. The NTD of the AR plays a key role in AR transactivation including androgen-independent activation of the AR in castration-resistant prostate cancer (CRPC) cells. We recently reported that amino acids (a.a.) 50-250 of the NTD are capable of modulating AR nucleocytoplasmic trafficking. To further explore the mechanism associated with a.a. 50-250, GFP pull-down assays were performed in C4-2 CRPC cells transfected with GFP tagged a.a. 50-250 of the AR. Mass spectrometry analysis of the pulled down proteins identified poly (A) binding protein cytoplasmic 1 (PABPC1) interaction with this region of the AR. In silico analysis of gene expression data revealed PABPC1 up-regulation in prostate cancer tissue specimens and this up-regulation correlates to increased disease recurrence. Co-immunoprecipitation assays confirmed the association of PABPC1 with a.a. 50-250 of the NTD of the AR. Knockdown of PABPC1 decreased nuclear AR protein levels and inhibited androgen activation of the AR target PSA in LNCaP and C4-2 cells. Additionally, knockdown of PABPC1 inhibited transactivation of the PSA promoter by NAR (AR lacking the LBD) and attenuated proliferation of AR-positive prostate cancer cells. These findings suggest that PABPC1 is a novel co-regulator of the AR and may be a potential target for blocking activation of the AR in CRPC.

No MeSH data available.


Related in: MedlinePlus