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Re: Inactivation of Androgen-Induced Regulator ARD1 Inhibits Androgen Receptor Acetylation and Prostate Tumorigenesis
URO-SCIENCE
2015
the target membrane receptors, which may reveal optimal models under physiologically relevant conditions. This study provides a novel comparison of expression signatures of prominent membrane receptors for prostate cancer targeting applying widely used prostate cancer cells grown in vitro and in vivo. These findings should be helpful in guiding the development of targeting strategies for imaging and therapeutic agents using membrane receptor signatures rather than single membrane bound targets. This approach should in turn overcome the difficulties often encountered when translating in vitro applications to preclinical models and when transitioning such applications toward clinical use. Anthony Atala, M.D.
Re: Inactivation of Androgen-Induced Regulator ARD1 Inhibits Androgen Receptor Acetylation and Prostate Tumorigenesis Z. Wang, Z. Wang, J. Guo, Y. Li, J. H. Bavarva, C. Qian, M. C. Brahimi-Horn, D. Tan and W. Liu Department of Genetics and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana Proc Natl Acad Sci U S A 2012; 109: 3053–3058.
Androgen signaling through androgen receptor (AR) is critical for prostate tumorigenesis. Given that AR-mediated gene regulation is enhanced by AR coregulators, inactivation of those coregulators is emerging as a promising therapy for prostate cancer (PCa). Here, we show that the N-acetyltransferase arrest-defect 1 protein (ARD1) functions as a unique AR regulator in PCa cells. ARD1 is up-regulated in human PCa cell lines and primary tumor biopsies. The expression of ARD1 was augmented by treatment with synthetic androgen (R1881) unless AR is deficient or is inhibited by AR-specific siRNA or androgen inhibitor bicalutamide (Casodex). Depletion of ARD1 by shRNA suppressed PCa cell proliferation, anchorage-independent growth, and xenograft tumor formation in SCID mice, suggesting that AR-dependent ARD1 expression is biologically germane. Notably, ARD1 was critical for transcriptionally regulating a number of AR target genes that are involved in prostate tumorigenesis. Furthermore, ARD1 interacted physically with and acetylated the AR protein in vivo and in vitro. Because AR-ARD1 interaction facilitated the AR binding to its targeted promoters for gene transcription, we propose that ARD1 functions as a unique AR regulator and forms a positive feedback loop for AR-dependent prostate tumorigenesis. Disruption of AR-ARD1 interactions may be a potent intervention for androgen-dependent PCa therapy. Editorial Comment: Androgen signaling, particularly the androgen receptor activity, has a crucial role in prostate cancer development. The primary role of androgen receptor in prostate cancer is believed to be regulating expression of the genes that are essential for prostate tumorigenesis. As a transcriptional factor, after binding to androgen the androgen receptor binds to specific DNA sequences and consequently recruits RNA polymerase II and a basal transcriptional complex for efficient transcription of androgen receptor target genes. Deregulation of the androgen receptor target genes has been shown to promote prostate cancer cell growth and tumorigenesis. In a genetic analysis of DNA damage response genes in prostate cancer it was previously found that ARD1 was not mutated, but rather upregulated in prostate cancer. ARD1 induces acetylation in a large group of proteins that contain the N-␣ or -acetylation sites. By acetylating specific substrate proteins, ARD1 has important roles in apoptosis, hypoxia, autophagy and cell proliferation. Significantly recent reports indicate that dysregulation of ARD1 is associated with tumorigenesis in a variety of human cancers, including colorectal, breast and lung. However, the role of ARD1 in prostate cancer remains unknown. In this study the authors identified ARD1 as a unique androgen induced androgen receptor regulator in prostate cancer. By overexpressing or silencing ARD1, it was demonstrated that ARD1 is crucial for androgen receptor mediated gene transcription, pros-
2016
URO-SCIENCE
tate cancer cell proliferation and xenograft tumor growth. Importantly the authors have revealed an important role of ARD1 in prostate tumorigenesis through its interaction with and acetylation of androgen receptor. The findings suggest that dysregulation of ARD1 may contribute to androgen receptor mediated gene transcription and prostate cancer development, and that ARD1 is a potential therapeutic target for prostate cancer. Anthony Atala, M.D.
Re: GPRC6A Regulates Prostate Cancer Progression M. Pi and L. D. Quarles Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee Prostate 2012; 72: 399 – 409.
Background: GPRC6A is a nutrient sensing GPCR that is activated in vitro by a variety of ligands, including amino acids, calcium, zinc, osteocalcin (OC), and testosterone. The association between nutritional factors and risk of prostate cancer, the finding of increased expression of OC in prostate cancer cells, and the association between GPRC6A and risk of prostate cancer in Japanese men implicates a role of GPRC6A in prostate cancer. Methods: We examined if GPRC6A is expressed in human prostate cancer cell lines and used siRNA-mediated knockdown GPRC6A expression in prostate cancer cells to explore the function of GPRC6A in vitro. To assess the role of GPRC6A in prostate cancer progression in vivo, we intercrossed Gprc6a(⫺/⫺) mice onto the TRAMP mouse prostate cancer model. Results: GPRC6A transcripts were markedly increased in prostate cancer cell lines 22Rv1, PC-3, and LNCaP, compared to the normal prostate RWPE-1 cell line. In addition, a panel of GPRC6A ligands, including calcium, OC, and arginine, exhibited in prostate cancer cell lines a dose-dependent stimulation of ERK activity, cell proliferation, chemotaxis, and prostate specific antigen and Runx2 gene expression. These responses were inhibited by siRNA-mediated knockdown of GPRC6A. Finally, transfer of Gprc6a deficiency onto a TRAMP mouse model of prostate cancer significantly retarded prostate cancer progression and improved survival of compound Gprc6a(⫺/⫺)/TRAMP mice. Conclusions: GPRC6A is a novel molecular target for regulating prostate growth and cancer progression. Increments in GPRC6A may augment the ability of prostate cancer cells to proliferate in response to dietary and bone derived ligands. Editorial Comment: The authors examined the expression and function of GPRC6A in prostate cancer progression in vitro and in vivo using a combination of molecular and mouse genetic approaches. They found that GPRC6A is expressed in normal prostate and is increased in cancer derived prostate cell lines. Bovine serum albumin coupled testosterone and OC stimulates ERK phosphorylation in HEK-293 cells transfected with GPRC6A, and in 22RV1 and PC-3 human prostate cancer cells expressing endogenous GPRC6A. Moreover, RNAi mediated knockdown of GPRC6A in prostate cancer cells inhibits ligand stimulated proliferation and chemotaxis in vitro. Finally, deletion of GPRC6A in the TRAMP mouse model of prostate cancer significantly retarded prostate cancer progression and improved survival. Based on these findings, the authors propose that GPRC6A may mediate the prostate response to nutrients, OC and nongenomic effects of androgens, and that targeting this receptor with an antagonist may provide a complementary strategy to treat androgen resistant prostate cancer. Anthony Atala, M.D.
2015
the target membrane receptors, which may reveal optimal models under physiologically relevant conditions. This study provides a novel comparison of expression signatures of prominent membrane receptors for prostate cancer targeting applying widely used prostate cancer cells grown in vitro and in vivo. These findings should be helpful in guiding the development of targeting strategies for imaging and therapeutic agents using membrane receptor signatures rather than single membrane bound targets. This approach should in turn overcome the difficulties often encountered when translating in vitro applications to preclinical models and when transitioning such applications toward clinical use. Anthony Atala, M.D.
Re: Inactivation of Androgen-Induced Regulator ARD1 Inhibits Androgen Receptor Acetylation and Prostate Tumorigenesis Z. Wang, Z. Wang, J. Guo, Y. Li, J. H. Bavarva, C. Qian, M. C. Brahimi-Horn, D. Tan and W. Liu Department of Genetics and Stanley S. Scott Cancer Center, Louisiana State University Health Sciences Center, New Orleans, Louisiana Proc Natl Acad Sci U S A 2012; 109: 3053–3058.
Androgen signaling through androgen receptor (AR) is critical for prostate tumorigenesis. Given that AR-mediated gene regulation is enhanced by AR coregulators, inactivation of those coregulators is emerging as a promising therapy for prostate cancer (PCa). Here, we show that the N-acetyltransferase arrest-defect 1 protein (ARD1) functions as a unique AR regulator in PCa cells. ARD1 is up-regulated in human PCa cell lines and primary tumor biopsies. The expression of ARD1 was augmented by treatment with synthetic androgen (R1881) unless AR is deficient or is inhibited by AR-specific siRNA or androgen inhibitor bicalutamide (Casodex). Depletion of ARD1 by shRNA suppressed PCa cell proliferation, anchorage-independent growth, and xenograft tumor formation in SCID mice, suggesting that AR-dependent ARD1 expression is biologically germane. Notably, ARD1 was critical for transcriptionally regulating a number of AR target genes that are involved in prostate tumorigenesis. Furthermore, ARD1 interacted physically with and acetylated the AR protein in vivo and in vitro. Because AR-ARD1 interaction facilitated the AR binding to its targeted promoters for gene transcription, we propose that ARD1 functions as a unique AR regulator and forms a positive feedback loop for AR-dependent prostate tumorigenesis. Disruption of AR-ARD1 interactions may be a potent intervention for androgen-dependent PCa therapy. Editorial Comment: Androgen signaling, particularly the androgen receptor activity, has a crucial role in prostate cancer development. The primary role of androgen receptor in prostate cancer is believed to be regulating expression of the genes that are essential for prostate tumorigenesis. As a transcriptional factor, after binding to androgen the androgen receptor binds to specific DNA sequences and consequently recruits RNA polymerase II and a basal transcriptional complex for efficient transcription of androgen receptor target genes. Deregulation of the androgen receptor target genes has been shown to promote prostate cancer cell growth and tumorigenesis. In a genetic analysis of DNA damage response genes in prostate cancer it was previously found that ARD1 was not mutated, but rather upregulated in prostate cancer. ARD1 induces acetylation in a large group of proteins that contain the N-␣ or -acetylation sites. By acetylating specific substrate proteins, ARD1 has important roles in apoptosis, hypoxia, autophagy and cell proliferation. Significantly recent reports indicate that dysregulation of ARD1 is associated with tumorigenesis in a variety of human cancers, including colorectal, breast and lung. However, the role of ARD1 in prostate cancer remains unknown. In this study the authors identified ARD1 as a unique androgen induced androgen receptor regulator in prostate cancer. By overexpressing or silencing ARD1, it was demonstrated that ARD1 is crucial for androgen receptor mediated gene transcription, pros-
2016
URO-SCIENCE
tate cancer cell proliferation and xenograft tumor growth. Importantly the authors have revealed an important role of ARD1 in prostate tumorigenesis through its interaction with and acetylation of androgen receptor. The findings suggest that dysregulation of ARD1 may contribute to androgen receptor mediated gene transcription and prostate cancer development, and that ARD1 is a potential therapeutic target for prostate cancer. Anthony Atala, M.D.
Re: GPRC6A Regulates Prostate Cancer Progression M. Pi and L. D. Quarles Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee Prostate 2012; 72: 399 – 409.
Background: GPRC6A is a nutrient sensing GPCR that is activated in vitro by a variety of ligands, including amino acids, calcium, zinc, osteocalcin (OC), and testosterone. The association between nutritional factors and risk of prostate cancer, the finding of increased expression of OC in prostate cancer cells, and the association between GPRC6A and risk of prostate cancer in Japanese men implicates a role of GPRC6A in prostate cancer. Methods: We examined if GPRC6A is expressed in human prostate cancer cell lines and used siRNA-mediated knockdown GPRC6A expression in prostate cancer cells to explore the function of GPRC6A in vitro. To assess the role of GPRC6A in prostate cancer progression in vivo, we intercrossed Gprc6a(⫺/⫺) mice onto the TRAMP mouse prostate cancer model. Results: GPRC6A transcripts were markedly increased in prostate cancer cell lines 22Rv1, PC-3, and LNCaP, compared to the normal prostate RWPE-1 cell line. In addition, a panel of GPRC6A ligands, including calcium, OC, and arginine, exhibited in prostate cancer cell lines a dose-dependent stimulation of ERK activity, cell proliferation, chemotaxis, and prostate specific antigen and Runx2 gene expression. These responses were inhibited by siRNA-mediated knockdown of GPRC6A. Finally, transfer of Gprc6a deficiency onto a TRAMP mouse model of prostate cancer significantly retarded prostate cancer progression and improved survival of compound Gprc6a(⫺/⫺)/TRAMP mice. Conclusions: GPRC6A is a novel molecular target for regulating prostate growth and cancer progression. Increments in GPRC6A may augment the ability of prostate cancer cells to proliferate in response to dietary and bone derived ligands. Editorial Comment: The authors examined the expression and function of GPRC6A in prostate cancer progression in vitro and in vivo using a combination of molecular and mouse genetic approaches. They found that GPRC6A is expressed in normal prostate and is increased in cancer derived prostate cell lines. Bovine serum albumin coupled testosterone and OC stimulates ERK phosphorylation in HEK-293 cells transfected with GPRC6A, and in 22RV1 and PC-3 human prostate cancer cells expressing endogenous GPRC6A. Moreover, RNAi mediated knockdown of GPRC6A in prostate cancer cells inhibits ligand stimulated proliferation and chemotaxis in vitro. Finally, deletion of GPRC6A in the TRAMP mouse model of prostate cancer significantly retarded prostate cancer progression and improved survival. Based on these findings, the authors propose that GPRC6A may mediate the prostate response to nutrients, OC and nongenomic effects of androgens, and that targeting this receptor with an antagonist may provide a complementary strategy to treat androgen resistant prostate cancer. Anthony Atala, M.D.