Steroid receptor coactivator-3 and cancer stem cells

描述（由申请人提供）：类固醇受体共激活因子-3 （SRC-3）是第二大过度表达的癌基因，高SRC-3表达与治疗耐药性密切相关，并降低无病生存期。相反，肿瘤抑制因子miR-34a的表达在癌症干细胞（CSCs）中被抑制，miR-34a的再表达抑制了CSCs的功能。阐明miR-34a在CSCs中的表达是如何被抑制的显然很重要。在本应用中，我们重点关注SRC-3对miR-34a的调控及其在癌症进展中的作用。有趣的是，SRC-3作为“协抑制因子”而不是“协激活因子”抑制miR-34a的表达。在乳腺癌中，SRC-3的表达与肿瘤分级、分期呈正相关，而与miR-34a的表达呈负相关，提示SRC-3、miR-34a的表达与乳腺癌的疾病状态存在因果关系。这是SRC-3“协阻遏因子”功能的第一篇报道，SRC-3作为“协阻遏因子”抑制miR-34a表达的意义和机制仍有待确定。我们的中心假设是SRC-3以环境和信号依赖的方式作为“协同抑制因子”抑制miR-34a表达并促进CSCs活性。本应用程序的目的是确定SRC-3的“协同抑制因子”功能的机制，并证明SRC-3- mir -34a通路在csc中的作用。我们将通过追求两个目标来实现我们的目标。目的1。鉴定致癌共激活因子SRC-3的“辅抑制因子”活性。尽管miR-34a作为肿瘤抑制因子很重要，但在csc中如何抑制miR-34a的表达尚不清楚。为了了解SRC-3如何抑制miR-34a，转录抑制因子X1 （RFX1）和SRC-3在S505的去磷酸化被确定为SRC-3“协抑制”功能的潜在决定因素。这是关于致癌“共激活因子”SRC-3的“共抑制因子”活性的第一篇报道，我们的目标是阐明SRC-3在S505位点的去磷酸化决定其与RFX1一起抑制miR-34a表达的“共抑制因子”功能的机制。目标2。定义SRC-3“协阻遏因子”活性的功能。MiR-34a是抑制CSCs功能的重要肿瘤抑制因子。SRC-3和RFX1被鉴定为miR-34a表达的新型抑制因子。我们的目的是证明SRC-3与RFX1的“协同抑制因子”活性通过抑制miR-34a的表达来促进CSCs的功能。我们的研究具有很高的创新性和意义。这表明SRC-3在CSCs富集的生态位中作为“协抑制因子”，通过抑制miR-34a来促进CSCs的功能。该研究首次揭示了SRC-3的“协抑制因子”功能依赖于转录抑制因子RFX1及其自身的去磷酸化。我们的研究发现了一种新的“协同抑制因子”活性，该活性控制scs中SRC-3的功能。这是我们确定可靶向SRC-3 CSCs通路的长期目标的重要一步，这将有助于开发抗CSCs疗法，以提高癌症患者的治疗反应和生存率。

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.