Androgen receptor as a regulator of ZEB2 expression and its implications in epithelial-to-mesenchymal transition in prostate cancer

Published on Jun 1, 2014in Endocrine-related Cancer4.8
· DOI :10.1530/ERC-13-0514
Sheeba Jacob6
Estimated H-index: 6
(ICMR: Indian Council of Medical Research),
Sumeet Nayak9
Estimated H-index: 9
(ICMR: Indian Council of Medical Research)
+ 5 AuthorsGeetanjali Sachdeva18
Estimated H-index: 18
(ICMR: Indian Council of Medical Research)
Sources
Abstract
Zinc finger E-box-binding protein 2 (ZEB2) is known to help mediate the epithelialto-mesenchymal transition, and thereby it facilitates cancer metastasis. This study was initiated to explore whether ZEB2 expression differs in prostate cancer (PCa, nZ7) and benign prostatic hyperplasia (BPH, nZ7) tissues. In PCa tissues, the levels of both immunoreactive ZEB2 and androgen receptor (AR) were found to be significantly higher (P!0.05) when compared with BPH tissues. Co-regulation of AR and ZEB2 prompted us to investigate the role of androgenic stimuli in ZEB2 expression. ZEB2 expression was found to be significantly (P!0.05) upregulated after androgen stimulation and downregulated following AR silencing in LNCaP cells, an androgen-dependent PCa cell line. This finding suggested AR as a positive regulator of ZEB2 expression in androgen-dependent cells. Paradoxically, androgen-independent (AI) cell lines PC3 and DU145, known to possess low AR levels, showed significantly (P!0.05) higher expression of ZEB2 compared with LNCaP cells. Furthermore, forced expression of AR in PC3 (PC3-AR) and DU145 (DU-AR) cells led to reductions in ZEB2 expression, invasiveness, and migration. These cells also exhibited an increase in the levels of E-cadherin (a transcriptional target of ZEB2). Co-transfection of AR and ZEB2 cDNA constructs prevented the decline in invasiveness and migration to a significant extent. Additionally, ZEB2 downregulation was associated with an increase in miR200a/miR200b levels in PC3-AR cells and with a decrease in miR200a/miR200b levels in AR-silenced LNCaP cells. Thus, AR acts as a positive regulator of ZEB2 expression in androgendependent cells and as a negative regulator in AI PCa cells.
📖 Papers frequently viewed together
2 Citations
6 Citations
References32
Newest
#1Kouji Izumi (UR: University of Rochester)H-Index: 8
#2Lei-Ya Fang (UR: University of Rochester)H-Index: 6
Last. Chawnshang Chang (UR: University of Rochester)H-Index: 110
view all 7 authors...
Increased CCL2 expression in prostate cancer (PCa) cells enhanced metastasis via macrophage recruitment. However, its linkage to androgen receptor (AR)-mediated PCa progression remains unclear. Here, we identified a previously unrecognized regulation: targeting AR with siRNA in PCa cells increased macrophage recruitment via CCL2 up-regulation, which might then result in enhancing PCa invasiveness. Molecular mechanism dissection revealed that targeting PCa AR with siRNA promoted PCa cell migratio...
136 CitationsSource
Proceedings: AACR 104th Annual Meeting 2013; Apr 6-10, 2013; Washington, DC Introduction: Approximately 10% to 15% of all sporadic colorectal cancers have microsatellite instability (MSI). MSI has not been well studied in Hispanics, an ethnic minority at high risk for colorectal cancer (CRC). Patients with MSI tumors present with better prognosis, higher 5-year survival and limited response to 5-FU based chemotherapy, compared to microsatellite stable (MSS) tumors. The aim of this study was to d...
1 CitationsSource
#1Tiancheng Liu (WSU: Washington State University)H-Index: 17
#2Lisa Y. Wu (WSU: Washington State University)H-Index: 12
Last. Clifford E. Berkman (WSU: Washington State University)H-Index: 28
view all 5 authors...
Emergence of androgen-independent cancer cells during androgen deprivation therapy presents a significant challenge to successful treatment outcomes in prostate cancer. Elucidating the role of androgen deprivation in the transition from an androgen-dependent to an androgen-independent state may enable the development of more effective therapeutic strategies against prostate cancer. Herein, we describe an in vitro model for assessing the effects of continuous androgen-deprivation on prostate canc...
40 CitationsSource
#1Vanessa Byles (BU: Boston University)H-Index: 8
#2Lijia Zhu (BU: Boston University)H-Index: 5
Last. Yan Dai (BU: Boston University)H-Index: 15
view all 7 authors...
The epithelial-to-mesenchymal transition (EMT) is a crucial program for the invasion and metastasis of epithelial tumors that involves loss of cell–cell adhesion and increased cell mobility; however, mechanisms underlying this transition are not fully elucidated. Here, we propose a novel mechanism through which the nicotinamide adenine dinucleotide-dependent histone deacetylase SIRT1 regulates EMT in prostate cancer cells through cooperation with the EMT inducing transcription factor ZEB1. We fo...
212 CitationsSource
#1Peng Ru (SLU: Saint Louis University)H-Index: 9
#2Robert SteeleH-Index: 81
Last. Ratna B. Ray (SLU: Saint Louis University)H-Index: 60
view all 6 authors...
Prostate cancer remains the second leading cause of cancer deaths among American men. Early diagnosis increases survival rate in patients; however, treatments for advanced disease are limited to hormone ablation techniques and palliative care. Thus, new methods of treatment are necessary for inhibiting prostate cancer disease progression. Here, we have shown that miRNA-29b (miR-29b) expression was lower in prostate cancer cells (PC3 and LNCaP) as compared with immortalized prostate epithelial ce...
142 CitationsSource
#1Dennis J. van de Wijngaart (EUR: Erasmus University Rotterdam)H-Index: 7
#2Hendrikus J. Dubbink (EUR: Erasmus University Rotterdam)H-Index: 31
Last. Guido Jenster (EUR: Erasmus University Rotterdam)H-Index: 66
view all 5 authors...
Androgens are key regulators of male sexual differentiation and essential for development and maintenance of male reproductive tissues. The androgens testosterone and dihydrotestosterone mediate their effect by binding to, and activation of the androgen receptor (AR). Upon activation, the AR is able to recognize specific DNA sequences in gene promoters and enhancers from where it recruits coregulators to orchestrate chromatin remodeling and transcription regulation. The number of proteins that b...
82 CitationsSource
#1Yuting Sun (Genentech)H-Index: 13
#2Bu-Er WangH-Index: 8
Last. Leisa JohnsonH-Index: 13
view all 12 authors...
Androgen deprivation is currently a standard-of-care, first-line therapy for prostate cancer in the United States. Although this regimen effectively regresses androgen-dependent disease, relapse often occurs in an androgen-independent manner and is associated with poor prognosis. Such castration-resistant prostate cancer represents a major clinical challenge, and the mechanisms underlying castration resistance are not fully understood. Epithelial–mesenchymal transition (EMT) is a key development...
260 CitationsSource
The zinc finger E-box binding protein 1 (ZEB1) transcription factor belongs to a two-member family of zinc-finger homeodomain proteins involved in physiological and pathological events mostly relating to cell migration and epithelial to mesenchymal transitions (EMTs). ZEB1 (also known as δEF1, zfhx1a, TCF8, and Zfhep) plays a key role in regulating such diverse processes as T-cell development, skeletal patterning, reproduction, and cancer cell metastasis. However, the factors that regulate its e...
19 CitationsSource
#1Biswajyoti Sahu (UH: University of Helsinki)H-Index: 15
#2Marko Laakso (UH: University of Helsinki)H-Index: 11
Last. Olli A. Jänne (UH: University of Helsinki)H-Index: 82
view all 15 authors...
High androgen receptor (AR) level in primary tumour predicts increased prostate cancer-specific mortality. However, the mechanisms that regulate AR function in prostate cancer are poorly known. We report here a new paradigm for the forkhead protein FoxA1 action in androgen signalling. Besides pioneering the AR pathway, FoxA1 depletion elicited extensive redistribution of AR-binding sites (ARBs) on LNCaP-1F5 cell chromatin that was commensurate with changes in androgen-dependent gene expression s...
251 CitationsSource
#1Orit Leshem (HUJI: Hebrew University of Jerusalem)H-Index: 1
#2Shalom Madar (Weizmann Institute of Science)H-Index: 23
Last. Raanan Berger (Sheba Medical Center)H-Index: 34
view all 15 authors...
Prostate cancer is the most common non-dermatologic malignancy in men in the Western world. Recently, a frequent chromosomal aberration fusing androgen regulated TMPRSS2 promoter and the ERG gene (TMPRSS2/ERG) was discovered in prostate cancer. Several studies demonstrated cooperation between TMPRSS2/ERG and other defective pathways in cancer progression. However, the unveiling of more specific pathways in which TMPRSS2/ERG takes part, requires further investigation. Using immortalized prostate ...
92 CitationsSource
Cited By23
Newest
#1Nicholas Mitsiades (BCM: Baylor College of Medicine)H-Index: 76
#2Salma Kaochar (BCM: Baylor College of Medicine)H-Index: 6
Based on pioneering work by Huggins, Hodges and others, hormonal therapies have been established as an effective approach for advanced prostate cancer (PC) for the past 8 decades. However, it quickly became evident that androgen deprivation therapy (ADT) via surgical or medical castration accomplishes inadequate inhibition of the androgen receptor (AR) axis, with clinical resistance inevitably emerging due to adrenal and intratumoral sources of androgens and other mechanisms. Early efforts to au...
2 CitationsSource
#1Bingpeng Deng (CSU: Central South University)
#2Xuan Tang (CSU: Central South University)
Last. Yong Wang (CSU: Central South University)
view all 3 authors...
Source
#1Ayesha A. Shafi (Thomas Jefferson University)H-Index: 5
#2Christopher McNair (Thomas Jefferson University)H-Index: 13
Last. Karen E. Knudsen (Thomas Jefferson University)H-Index: 68
view all 20 authors...
Mechanisms regulating DNA repair processes remain incompletely defined. Here, the circadian factor CRY1, an evolutionally conserved transcriptional coregulator, is identified as a tumor specific regulator of DNA repair. Key findings demonstrate that CRY1 expression is androgen-responsive and associates with poor outcome in prostate cancer. Functional studies and first-in-field mapping of the CRY1 cistrome and transcriptome reveal that CRY1 regulates DNA repair and the G2/M transition. DNA damage...
3 CitationsSource
#1R. K. Tiwari (IITK: Indian Institute of Technology Kanpur)H-Index: 4
#2Nishat Manzar (IITK: Indian Institute of Technology Kanpur)H-Index: 2
Last. Bushra Ateeq (IITK: Indian Institute of Technology Kanpur)H-Index: 25
view all 3 authors...
Despite the current advances in the treatment for prostate cancer, the patients often develop resistance to the conventional therapeutic interventions. Therapy-induced drug resistance and tumor progression have been associated with cellular plasticity acquired due to reprogramming at the molecular and phenotypic levels. The plasticity of the tumor cells is mainly governed by two factors: cell-intrinsic and cell-extrinsic. The cell-intrinsic factors involve alteration in the genetic or epigenetic...
5 CitationsSource
#1Julia Jansen (MLU: Martin Luther University of Halle-Wittenberg)H-Index: 1
#2Thomas Greither (MLU: Martin Luther University of Halle-Wittenberg)H-Index: 18
Last. Hermann M. Behre (MLU: Martin Luther University of Halle-Wittenberg)H-Index: 52
view all 3 authors...
The development, homeostasis, or increase of the adipose tissue is driven by the induction of the adipogenic differentiation (adipogenesis) of undifferentiated mesenchymal stem cells (MSCs). Adipogenesis can be inhibited by androgen stimulation of these MSCs resulting in the transcription initiation or repression of androgen receptor (AR) regulated genes. AR not only regulates the transcription of protein-coding genes but also the transcription of several non-coding microRNAs involved in the pos...
2 CitationsSource
#1Xingtao LiH-Index: 1
#2Chunhong LiH-Index: 1
Last. Chunhui QiH-Index: 1
view all 7 authors...
Introduction: Non-small cell lung cancer (NSCLC) is a common cause of deaths all over the world. Emerging evidence has indicated that microRNA (miR) play key roles in NSCLC progression. We aimed to determine the functions of miR-129 in NSCLC. miR-129 was dramatically downregulated in NSCLC tissue samples and cells. The decreased miR-129 was found to be associated with poorer prognosis and malefic phenotype of NSCLC patients. We demonstrated that miR-129 upregulation could inhibit NSCLC cell grow...
7 CitationsSource
#1Sushama Gadkar (National Institute for Research in Reproductive Health)H-Index: 7
#2Shardool Nair (National Institute for Research in Reproductive Health)H-Index: 2
Last. Geetanjali Sachdeva (National Institute for Research in Reproductive Health)H-Index: 18
view all 8 authors...
: The plasma membrane (PM) is considered as a major druggable site. More than 50% of the existing drugs target PM proteins. In the wake of emerging data indicating a key role of estrogens in prostate cancer (PCa) pathogenesis, the study was undertaken to explore whether the estrogen binding sites exist on the PM and if such sites are functionally relevant in PCa. Estradiol (E2) binding to the PM was detected in androgen-dependent (LNCaP), androgen-independent (PC3, DU145) PCa cell lines, nontumo...
4 CitationsSource
#1Galina Gritsina (NU: Northwestern University)H-Index: 8
#2Wei Qiang Gao (SJTU: Shanghai Jiao Tong University)H-Index: 1
Last. Jindan Yu (NU: Northwestern University)H-Index: 50
view all 3 authors...
Androgen receptor (AR), a hormonal transcription factor, plays important roles during prostate cancer progression and is a key target for therapeutic interventions. While androgen-deprivation therapies are initially successful in regressing prostate tumors, the disease ultimately comes back as castration-resistant prostate cancer (CRPC) or at the late stage as neuroendocrine prostate cancer (NEPC). CRPC remains largely dependent on hyperactive AR signaling in the milieu of low androgen, while NE...
8 CitationsSource
#1Jiayi Zhang (Nanjing Medical University)H-Index: 7
#2Hengcheng Zhang (Nanjing Medical University)H-Index: 4
Last. Min Gu (Nanjing Medical University)H-Index: 16
view all 7 authors...
Background: The microRNA (miRNA) miR-200c-3p is involved in the tumorigenesis and progression of a variety of cancers. However, the underlying regulatory role of miR-200c-3p in prostate cancer (PCa) remains unclear. Methods: Online databases including Oncomine, Linkedomics and StarBase were used to investigate the clinical significance of miR-200c-3p, along with associated gene targets. PCa tissues and adjacent normal tissues were used for the detection of miR-200c-3p expression. A lentivirus ov...
11 CitationsSource
#1Daksh Thaper (UBC: University of British Columbia)H-Index: 10
#2Sepideh Vahid (Vancouver Prostate Centre)H-Index: 2
Last. Amina Zoubeidi (UBC: University of British Columbia)H-Index: 47
view all 3 authors...
Progression to the malignant state is fundamentally dependent on transcriptional regulation in cancer cells. Optimum abundance of cell cycle proteins, angiogenesis factors, immune evasion markers, etc. is needed for proliferation, metastasis or resistance to treatment. Therefore, dysregulation of transcription factors can compromise the normal prostate transcriptional network and contribute to malignant disease progression.
1 CitationsSource