Steroid receptor coactivator-3 and cancer stem cells

描述(申请人提供)：类固醇受体辅活化子-3(SRC-3)是第二高表达的癌基因，SRC-3的高表达与对治疗的抵抗密切相关，并降低无病生存率。相反，肿瘤抑制基因miR-34a在肿瘤干细胞中的表达受到抑制，而miR-34a的重新表达则抑制了肿瘤干细胞的功能。阐明miR-34a在CSCs中的表达是如何被抑制的显然是很重要的。在本应用中，我们重点研究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作为抑制miR-34a表达的“共抑制因子”而不是“辅助激活因子”发挥作用。乳腺癌组织中SRC-3和miR-34a的表达与肿瘤分级和分期呈正相关，而与miR-34a的表达呈负相关，提示SRC-3和miR-34a的表达与乳腺癌的病情有因果关系。这是有关SRC-3‘corepressor’功能的首次报道，SRC-3作为‘corepressor’功能抑制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以一种上下文和信号依赖的方式发挥‘协同抑制物’的作用，抑制miR-34a的表达，促进CSCs的活性。本应用的目的是确定SRC-3‘corepressor’功能的机制，并证明SRC-3-miR-34a通路在CSCs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.从致癌辅活化子SRC-3中鉴定出一种辅抑制子活性。尽管miR-34a作为一种重要的肿瘤抑制因子，但其在CSCs中的表达如何被抑制尚不清楚。为了了解SRC-3是如何抑制miR-34a的，转录抑制调控因子X1(RFX1)和SRC-3在S505的去磷酸化被确定为SRC-3‘corepressor’功能的潜在决定因素。这是首次报道SRC-3的“辅阻遏子”活性，我们的目的是阐明SRC-3在S505的去磷酸化调控其与RFX1的“辅阻遏子”功能从而抑制miR-34a表达的机制。目的2.明确SRC-3‘辅阻遏子’活性的功能。MIR-34a是一种重要的肿瘤抑制因子，可以抑制CSCs的功能。SRC-3和RFX1被鉴定为miR-34a表达的新抑制因子。我们的目的是证明SRC-3与RFX1的协同抑制物活性通过抑制miR-34a的表达来促进CSCs的功能。我们的研究具有很强的创新性和重要意义。这表明SRC-3在CSCs丰富的生态位中发挥着‘辅抑制子’的作用，通过抑制miR-34a来促进CSCs的功能。首次揭示了SRC-3的辅阻遏子功能依赖于转录抑制子RFX1及其自身的去磷酸化。我们的研究发现了一种新的‘核心抑制物’活性，它调控着CSCs中SRC-3的功能。这是朝着我们确定靶向SRC-3 CSCs途径的长期目标迈出的重要一步，该途径将有助于开发抗CSCs疗法，以提高癌症患者的治疗反应和存活率。

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.