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REVIEW Increased Androgen Receptor Transcription: a Cause of Castration R25 REVIEW Increased androgen receptor transcription: a cause of castration-resistant prostate cancer and a possible therapeutic target Masaki Shiota, Akira Yokomizo and Seiji Naito Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan (Correspondence should be addressed to S Naito; Email: [email protected]) Abstract Few effective therapies exist for the treatment of castration-resistant prostate cancer (CRPC). Recent evidence suggests that CRPC may be caused by augmented androgen/androgen receptor (AR) signaling, generally involving AR overexpression. Aberrant androgen/AR signaling associated with AR overexpression also plays a key role in prostate carcinogenesis. Although AR overexpression could be attributed to gene amplification, only 10–20% of CRPCs exhibit AR gene amplification, and aberrant AR expression in the remaining instances of CRPC is thought to be attributed to transcriptional, translational, and post-translational mechanisms. Overexpression of AR at the protein level, as well as the mRNA level, has been found in CRPC, suggesting a key role for transcriptional regulation of AR expression. Since the analysis of the AR promoter region in the 1990s, several transcription factors have been reported to regulate AR transcription. In this review, we discuss the molecules involved in the control of AR gene expression, with emphasis on its transcriptional control by transcription factors in prostate cancer. We also consider the therapeutic potential of targeting AR expression. Journal of Molecular Endocrinology (2011) 47, R25–R41 Introduction abnormalities of the AR itself (AR mutation and overexpression) and/or its related molecules (AR The androgen/androgen receptor (AR) signaling cofactors). Furthermore, several kinds of AR splice pathway is known to play a critical role in prostate variants displaying significant constitutive activity in the tumorigenesis and prostate cancer (PCa) progression. absence of ligand-binding have recently been reported Androgen-deprivation therapy (ADT) either reduces by several laboratories (Dehm et al. 2008, Guo et al. the production of androgens by surgical or medical 2009, Hu et al. 2009, Sun et al. 2010). Many studies have castration, or interferes with the activity of the AR shown that progression to CRPC is associated with AR through the use of anti-androgens (Miyamoto et al. overexpression, and that AR inhibition represses tumor 2004). ADT is initially effective in about 90% of PCa growth in PCa, even in CRPC (Gregory et al. 1998, cases, but these eventually circumvent ADT and emerge Zegarra-Moro et al. 2002, Chen et al. 2004a,b, Scher & as castration-resistant PCa (CRPC; Roy-Burman et al. Sawyers 2005). Less than 10% of CRPC cases were 2005). However, the androgen/AR signaling pathway found to possess somatic AR gene mutations (Taplin remains a key determinant of cell proliferation in et al. 2003). In addition, the AR is upregulated in most CRPC, despite low levels of available androgens CRPCs, of which only 10–20% exhibit amplification of following ADT (Litvinov et al. 2003). The reactivation the AR gene (Linja et al. 2001), indicating that of the androgen/AR signaling pathway in CRPC has increased AR expression in CRPC may result from been attributed to a number of mechanisms, including factors other than gene amplification. The molecular AR hypersensitivity, local intracrine production of mechanisms underpinning the aberrant AR expression androgens, promiscuous activation of the AR by have thus been intensively investigated as a potential adrenal androgens, non-androgenic steroids and even source of novel therapeutic targets. anti-androgens, and activation of the AR by growth Although the expression of proteins, including AR factors and cytokines (Debes & Tindall 2004, Titus protein, is regulated by various steps (transcription, et al.2005). These phenomena may result from translation, and post-translational control), the Journal of Molecular Endocrinology (2011) 47, R25–R41 DOI: 10.1530/JME-11-0018 0952–5041/11/047–R25 q 2011 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.org Downloaded from Bioscientifica.com at 09/29/2021 06:01:58AM via free access R26 M SHIOTA Journal of Molecular Endocrinology Table 1 Transcription factor-related factors regulating human androgen receptor (AR) expression in prostate cancer Gene Direct Factor classification Gene function Cells Effect or indirect Supposed mechanism References and others CREB Transcription factor Induction of genes in response LNCaP C Direct Binding to CRE site Mizokami et al. (1994) to hormonal stimulation of the cAMP pathway . Myc Transcription factor Cell cycle progression, apoptosis, Vitro C Direct Binding to E-box Grad et al. (1999) AR overexpression in prostate cancer (2011) and cellular transformation Myc Transcription factor Cell cycle progression, apoptosis, LNCaP C Indirect Binding to E-box Lee et al. (2009) 47, and cellular transformation c-Jun Transcription factor Transforming gene LNCaP K Direct Binding to TRE site Pan et al. (2003) 25–41 c-Jun Transcription factor Transforming gene LNCaP K Direct Binding to TRE site Yuan et al. (2004) Sp1 Transcription factor Constitutive induction of genes Vitro C Direct Binding to GC-box Faber et al. (1993) Sp1 Transcription factor Constitutive induction of genes LNCaP C Direct Binding to GC-box Yuan et al. (2005) p53 Transcription factor Cell cycle arrest, apoptosis, LNCaP K Direct Binding to p53-binding site Alimirah et al. (2007) senescence, DNA repair, and metabolism Foxo3a Transcription factor Trigger for apoptosis LNCaP C Direct Binding to Foxo-response Yang et al. (2005) element LEF1 Transcription factor Hair cell differentiation, follicle LNCaP C Direct Binding to LEF/TCF-binding Yang et al. (2006) morphogenesis, and cellular site transformation LEF1 Transcription factor Hair cell differentiation, follicle LNCaP, C Direct Binding to LEF/TCF-binding Li et al. (2009) morphogenesis, and cellular AI-LNCaP site transformation Wnt-1 Cytokine Oncogenesis and developmental LNCaP C Indirect Activation of b-catenin Yang et al. (2006) processes b-Catenin Signal transduction Cell growth and adhesion LNCaP C Direct Activation of LEF1 and Yang et al. (2006) LEF1 complex Pura Transcription factor DNA replication and transcription LNCaP, K Direct Binding to suppressor element Wang et al. (2008) AI-LNCaP (ARS) binding sites NFkB Transcription factor Cellular transformation and LNCaP C Direct Binding to NFkB-binding site Zhang et al. (2009) inflammation Downloaded fromBioscientifica.com at09/29/202106:01:58AM Twist1 Transcription factor Differentiation, epithelial– LNCaP, C Direct Binding to E-box Shiota et al. (2010) mesenchymal transition 22Rv1, CxR E2F1 Transcription factor Cell cycle progression LNCaP K Direct Binding to E2F-binding site Davis et al. (2006) E2F1, E2F3 Transcription factor Cell cycle progression LNCaP C Direct Binding to E2F-binding site Sharma et al. (2010) Rb1 Transcription cofactor Cell cycle arrest and tumor LNCaP, K Direct Inhibition of E2F1 Sharma et al. (2010) suppressor LAPC-4 transactivation www.endocrinology-journals.org SREBP-1 Transcription factor Sterol biosynthesis LNCaP, C Direct Binding to sterol regulatory Huang et al. (2010) C4-2 element b2-Microglobulin Membrane protein Endocytosis of iron LNCaP, C Indirect Activation of SREBP-1 Huang et al. (2010) C4-2 Interleukin-8 Cytokine Inflammation LNCaP, C Indirect Activation of NFkB and AP-1 Seaton et al. (2008) 22Rv1 Endothelin-1 Hormone Vasoconstrictor LNCaP C Indirect Activation of Myc Lee et al. (2009) via freeaccess (continued) AR overexpression in prostate cancer . M SHIOTA and others R27 transcriptional step is generally thought to play a critical role in gene expression. In addition, AR overexpression has been detected at both the protein . (2010) . (2010) and mRNA levels in CRPC, suggesting that transcrip- . (2009) . (2005) . (2002) . (2009) . (2009) et al et al tional regulation of the AR gene is at least one of the et al et al et al et al et al major causes of AR dysregulation. In this review, we therefore summarize the factors involved in AR Kang Adam Kang Emami Zhang Hoshino Hoshino expression,withanemphasisontranscriptional regulation by transcription factors in PCa (Table 1). Furthermore, we also discuss the therapeutic potential of targeting AR expression for the treatment of PCa and CRPC, by considering the agents involved in the regulation of AR expression (Table 2). Band Band k k Transcriptional regulation complex c-myc c-myc Transcriptional control is thought to play a key role in the expression of a wide variety of genes, including AR. Transcription factors bind to DNA in a sequence- specific manner for each transcription factor, and Direct or indirect Supposed mechanismIndirect References Activation of Smads Indirect Inhibition of ARDirect transcription Activation of AR transcription Indirect Inhibition of LEF1 and LEF1 Direct Inhibition of AR transactivation Indirect Activation of NF Indirect Activation of NF positively or negatively affect gene expression through the control of transcription. The human AR is encoded by a single copy gene located on the X-chromosome. C K C K K C C Two major mRNAs of 11 and 7.5 kb are transcribed from this gene, regulated by cis-acting elements in its promoter region. The human AR promoter region lacks a TATA-box and a CCAAT-box, and the binding LNCaP LNCaP LNCaP sites for several transcription factors have
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