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

• 批准号: 8757078
• 负责人: Ray-Chang Wu
• 金额: $ 20.68万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-16 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8757078
• 关键词: Cancer Patient; Cancer Relapse; Cell physiology; Colorectal Cancer; Development; Diagnostic Neoplasm Staging; Dimensions; Disease; Disease-Free Survival; Goals; Health; Human; Knowledge; Malignant Neoplasms; Malignant neoplasm of prostate; MicroRNAs; Mission; Molecular; Mus; Neoplasm Metastasis; Oncogenes; Oncogenic; Pathway interactions; Patients; Phosphorylation; Quality of life; Regulation; Reporting; Research; Resistance; Role; Signal Transduction; Somatic Cell; Staging; Steroid Receptors; Testing; Transcription Coactivator; Transcription Repressor/Corepressor; Tumor Suppressor Proteins; Tumor stage; cancer cell; cancer stem cell; cancer therapy; driving force; embryonic stem cell; improved; innovation; insight; malignant breast neoplasm; novel; overexpression; programs; public health relevance; self-renewal; stem cell therapy; therapy resistant; treatment response; tumor; tumor progression

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.

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.