Steroid receptor coactivator-3 and cancer stem cells

类固醇受体辅激活因子3和癌症干细胞

基本信息

批准号：
8928092
负责人：
Ray-Chang Wu
金额：
$ 17.24万
依托单位：
GEORGE WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-16 至 2017-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Steroid receptor coactivator-3 (SRC-3) is the second most overexpressed oncogenes and high SRC-3 expression correlates well with resistance to therapy and reduces disease free survival. In contrast, expression of tumor suppressor miR-34a is suppressed in cancer stem cells (CSCs), and re-expression of miR-34a inhibits CSCs function. Elucidating how expression of miR-34a is suppressed in CSCs is clearly important. In this application, we focus on the regulation of miR-34a by SRC-3 and its role in cancer progression. Interestingly, SRC-3 functions as a 'corepressor' and not a 'coactivator' to suppress miR-34a expression. Expression of SRC-3 is positively correlated with tumor grades and stages, but inversely correlated with expression of miR-34a in breast cancer, suggesting a causal relationship between SRC-3 and miR-34a expression and the disease state of breast cancer. This is the first report of a 'corepressor' function of SRC-3, the significance and the mechanism whereby SRC-3 functions as a 'corepressor' to suppress expression of miR-34a remains to be identified. Our central hypothesis is that SRC-3 functions as a 'corepressor' in a context- and signaling-dependent manner to suppress miR-34a expression and promote CSCs activity. The objective of this application is to identify the mechanism which dictates the 'corepressor' function of SRC-3, and to demonstrate the role of SRC-3-miR-34a pathway in CSCs. We will achieve our objective by pursuing two aims. Aim 1. Identify a 'corepressor' activity from oncogenic coactivator SRC-3. Despite its importance as a tumor suppressor, how expression of miR-34a is suppressed in CSCs is not known. To understand how miR-34a is suppressed by SRC-3, transcription repressor regulatory factor X1 (RFX1) and de- phosphorylation of SRC-3 at S505 were identified as potential determinants for the 'corepressor' function of SRC-3. This is the first report of a 'corepressor' activity from an oncogenic 'coactivator' SRC-3, our objective is to elucidate the mechanism by which de-phosphorylation of SRC-3 at S505 dictates its 'corepressor' function with RFX1 to suppress miR-34a expression. Aim 2. Define the function of SRC-3 'corepressor' activity. MiR-34a is an important tumor suppressor that inhibits CSCs function. SRC-3 and RFX1 are identified to be novel suppressors of miR-34a expression. Our objective of this aim is to demonstrate that the 'corepressor' activity of SRC-3 with RFX1 promotes CSCs function by suppressing miR-34a expression. Our study is highly innovative and significant. It demonstrates that SRC-3 functions as a 'corepressor' in the CSCs-enriched niche to promote CSCs function by suppressing miR-34a. It is the first to reveal the 'corepressor' function of SRC-3 depends on transcriptional repressor RFX1 and its own de-phosphorylation. Our study uncovers a novel 'corepressor' activity that governs the function of SRC-3 in CSCs. This is a significant step toward our long-term goal of identifying a targetable SRC-3 CSCs pathway that will be instrumental for development of anti-CSCs therapy to improve treatment response and survival of cancer patients.

描述（由申请人提供）：类固醇受体共激活剂3（SRC-3）是第二高表达的癌基因，高SRC-3表达与对治疗的耐药性和降低无疾病的生存良好相关。相反，肿瘤抑制器miR-34a的表达在癌细胞（CSC）中抑制，而miR-34a的重新表达抑制了CSC的功能。阐明在CSC中如何抑制miR-34a的表达显然很重要。在此应用中，我们专注于SRC-3对miR-34a的调节及其在癌症进展中的作用。有趣的是，SRC-3充当“ corepressor”，而不是抑制miR-34a表达的“共激活因子”。 SRC-3的表达与肿瘤成绩和阶段呈正相关，但与乳腺癌中miR-34a的表达成反比，表明SRC-3与miR-34a表达与乳腺癌的疾病之间存在因果关系。这是SRC-3的“ CorePressor”函数的第一个报告，SRC-3的“核心”功能是SRC-3作为抑制miR-34a表达的“ corepressor”的重要性和机制。我们的中心假设是SRC-3在上下文和信号依赖性方式中充当“核心压力”，以抑制miR-34a表达并促进CSCS活性。该应用的目的是确定决定SRC-3的“ CorePressor”功能的机制，并证明SRC-3-MIR-34A途径在CSC中的作用。我们将通过实现两个目标来实现我们的目标。 AIM 1。从致癌共激活因子SRC-3中确定“ Corepressor”活性。尽管它作为肿瘤抑制剂的重要性，但在CSC中抑制miR-34a的表达方式尚不清楚。为了了解如何通过SRC-3抑制miR-34a，SRC-3的转录阻遏调节因子X1（RFX1）和SRC-3在S505处的磷酸化是SRC-3的“ Corepressor”功能的潜在决定因素。这是从致癌'共激活器'SRC-3中的“核心压力”活性的第一份报告，我们的目标是阐明S505处SRC-3的磷酸化的机制，该机制决定了其“ Corepressor”功能，以抑制MIR-34A表达。 AIM 2。定义SRC-3“ CorePressor”活动的功能。 miR-34a是抑制CSC功能的重要肿瘤抑制剂。 SRC-3和RFX1被确定为miR-34a表达的新型抑制剂。我们的目的是证明SRC-3与RFX1的“ CorePressor”活性通过抑制miR-34a表达来促进CSC的功能。我们的研究具有很高的创新性和重要意义。它表明SRC-3在富含CSCS的利基市场中充当“ Corepressor”，从而通过抑制miR-34a来促进CSC的功能。它是第一个揭示SRC-3的“ CorePressor”函数的功能，取决于转录抑制剂RFX1及其自身的去磷酸化。我们的研究发现了一种新型的“ Corepressor”活性，该活性控制着SRC-3在CSC中的功能。这是朝着我们的长期目标迈出的重要一步，即确定可靶向的SRC-3 CSC途径，该途径将对抗CSC疗法的发展起为改善癌症患者的治疗反应和存活而起作用。