SRC-3 Is Required for Prostate Cancer Cell Proliferation and Survival

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030, USA.
Cancer Research (Impact Factor: 9.33). 10/2005; 65(17):7976-83. DOI: 10.1158/0008-5472.CAN-04-4076
Source: PubMed


Prostate cancer is the most common cancer in men in America. Currently, steroid receptor coactivators have been proposed to mediate the development and progression of prostate cancer, at times in a steroid-independent manner. Steroid receptor coactivator-3 (SRC-3, p/CIP, AIB1, ACTR, RAC3, and TRAM-1) is a member of the p160 family of coactivators for nuclear hormone receptors including the androgen receptor. SRC-3 is frequently amplified or overexpressed in a number of cancers. However, the role of SRC-3 in cancer cell proliferation and survival is still poorly understood. In this study, we show that SRC-3 is overexpressed in prostate cancer patients and its overexpression correlates with prostate cancer proliferation and is inversely correlated with apoptosis. Consistent with patient data, we have observed that reduction of SRC-3 expression by small interfering RNA decreases proliferation, delays the G1-S transition, and increases cell apoptosis of different prostate cancer cell lines. Furthermore, with decreased SRC-3 expression, proliferating cell nuclear antigen and Bcl-2 expression, as well as bromodeoxyuridine incorporation in prostate cancer cells are reduced. Finally, knockdown of SRC-3 with inducible short hairpin RNA expression in prostate cancer cells decreased tumor growth in nude mice. Taken together, these findings indicate that SRC-3 is an important regulator of prostate cancer proliferation and survival.

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    • "AIB1 interacts with nuclear receptors and certain other transcription factors, recruits histone acetyltransferases and methyltransferases for chromatin remodeling, and facilitates target gene transcription. It is correlated with increased cancer cell proliferation, survival, migration, and invasiveness, all of which play important roles in the progression of many cancers such as prostate cancer (Zhou et al. 2005), breast cancer (Anzick et al. 1997), colorectal cancer (Mo et al. 2015; Xie et al. 2005), and hepatocellular carcinoma (Xu et al. 2010). AIB1 can interact with nuclear receptors and other transcription factors to regulate the expression of their target genes involved in many signaling pathways, including ERa, EGFR, Akt, MAPK, E2F1, C/EBPb, NFjB , HER2/neu, PEA3, and CBP/p300 (Chen et al. 1997; Kishimoto et al. 2005; Long et al. 2012; Long et al. 2010; Louie et al. 2004; Wu et al. 2002; Yan et al. 2006a, b). "
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    ABSTRACT: Amplified in breast cancer 1 (AIB1), also known as steroid receptor coactivator 3 (SRC-3), is a transcriptional coactivator that interacts with nuclear receptors and other transcription factors to enhance their effects on target gene transcription. AIB1, which acts as a major oncogene, is highly expressed in many human cancers, and has been demonstrated to be a key regulator for tumor initiation, progression, metastasis, invasion, and survival. Recruitment of the transcriptional factor CBP/p300 by CBP/p300-interaction domain (CID) of AIB1 is essential for its transcriptional activation function. In this research, we isolated a DNA aptamer AY-3 that binds to AIB1-CID from a random oligonucleotide library using in vitro screening technology-Systematic Evolution of Ligands by EXponential enrichment (SELEX). The binding affinity of the aptamer to AIB1-CID fusion protein is in the nanomolar range. More importantly, the aptamer was found to disrupt in the interaction between p300 and AIB1. This aptamer has great potential to serve as a therapeutic agent for cancer by inhibiting the coactivation of AIB1.
    Journal of Molecular Evolution 10/2015; DOI:10.1007/s00239-015-9703-y · 1.68 Impact Factor
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    • "It was reported that SRC-3 protein was overexpressed in 38% of tumor samples of prostate cancer [8]. Another study showed that SRC-3 expression is required for prostate cancer cell proliferation and survival, and its levels correlated with Prostate Specific Antigen (PSA) [9]. These studies suggest an important role of SRC-3 in prostate cancer formation. "

    Journal of Cancer Therapy 01/2015; 06(10):841-848. DOI:10.4236/jct.2015.610092
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    • "The persistent epithelial proliferation observed in the SRC-2:OE endometrium leaves open the question of whether this tissue is predisposed to tumorigenesis. Addressing this question is important since overexpression of SRC-2 (as shown for other members of the SRC family [3], [18]–[20], [22], [23], [58], [65]) is linked to the causation and/or progression of a number of cancer types [4], [17], [21]. In the case of the human endometrium, elevation of SRC expression levels has been correlated with endometrial hyperplasia and cancer [36]–[39] and with endometrial samples biopsied from patient groups predisposed to endometrial tumorigenesis [29]–[31]. "
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    ABSTRACT: As pleiotropic coregulators, members of the p160/steroid receptor coactivator (SRC) family control a broad spectrum of transcriptional responses that underpin a diverse array of physiological and pathophysiological processes. Because of their potent coregulator properties, strict controls on SRC expression levels are required to maintain normal tissue functionality. Accordingly, an unwarranted increase in the cellular levels of SRC members has been causally linked to the initiation and/or progression of a number of clinical disorders. Although knockout mouse models have underscored the critical non-redundant roles for each SRC member in vivo, there are surprisingly few mouse models that have been engineered to overexpress SRCs. This deficiency is significant since SRC involvement in many of these disorders is based on unscheduled increases in the levels (rather than the absence) of SRC expression. To address this deficiency, we used recent mouse technology that allows for the targeted expression of human SRC-2 in cells which express the progesterone receptor. Through cre-loxP recombination driven by the endogenous progesterone receptor promoter, a marked elevation in expression levels of human SRC-2 was achieved in endometrial cells that are positive for the progesterone receptor. As a result of this increase in coregulator expression, female mice are severely subfertile due to a dysfunctional uterus, which exhibits a hypersensitivity to estrogen exposure. Our findings strongly support the proposal from clinical observations that increased levels of SRC-2 are causal for a number of endometrial disorders which compromise fertility. Future studies will use this mouse model to decipher the molecular mechanisms that underpin the endometrial defect. We believe such mechanistic insight may provide new molecular descriptors for diagnosis, prognosis, and/or therapy in the clinical management of female infertility.
    PLoS ONE 06/2014; 9(6):e98664. DOI:10.1371/journal.pone.0098664 · 3.23 Impact Factor
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