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Role of SAP30 in hypoxia inducible factor activation and breast cancer progression

SAP30 在缺氧诱导因子激活和乳腺癌进展中的作用

基本信息

批准号：
10542338
负责人：
Weibo Luo
金额：
$ 36.32万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-12-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10542338
关键词：
Address BRCA1 gene Binding Bioinformatics Breast Cancer Cell Breast Cancer Model Breast Cancer Patient Breast Cancer cell line Breast cancer metastasis Cancer Biology Cancer Cell Growth Cancer Model Cell Survival Cessation of life Collaborations Collagen Data Development Disease Distant Distant Metastasis EP300 gene ERBB2 gene Epigenetic Process Extracellular Matrix Foundations Gene Expression Genes Genetic Genetic Transcription Goals Growth Histone Acetylation Human Hypoxia Hypoxia Inducible Factor Image In Vitro Invaded Knock-out Knockout Mice Malignant Neoplasms Mammary Neoplasms Mediating Metastatic Neoplasm to the Lung Molecular Mus Neoplasm Metastasis Oncogenic Organ Outcome Pathologist Patients Phenocopy Phenotype Play Process Proteins RNA Polymerase II Regulation Regulator Genes Research Response Elements Role Solid Specificity TP53 gene Therapeutic Tissues Tumor Promotion Up-Regulation Xenograft procedure aggressive breast cancer angiogenesis bHLH-PAS factor HLF breast cancer progression breast cancer survival cDNA Arrays cancer subtypes cell motility data mining hypoxia inducible factor 1 improved insight malignant breast neoplasm mortality mouse model new therapeutic target novel p300/CBP-Associated Factor promoter recruit response selective expression trait transcription factor triple-negative invasive breast carcinoma tumor tumor growth tumor hypoxia tumor microenvironment tumor progression

项目摘要

Tumor metastasis causes a high mortality of patients with triple-negative breast cancer (TNBC), but its underlying mechanism remains unknown. Emerging studies showed that dysregulated gene transcription mediates TNBC malignancy and tumor microenvironment is one of the critical regulators of gene dysregulation. Hypoxia-inducible factors (HIFs), mainly HIF-1 and HIF-2, are the master transcriptional regulators in response to hypoxia, a common feature of the tumor microenvironment, and activate their downstream target genes to regulate many key processes in cancer biology, including angiogenesis, extracellular matrix remodeling, cell migration/invasion, leading to TNBC progression and metastasis. Thus, understanding fundamental regulation of HIF transcriptional activity would uncover the mechanism of TNBC progression and metastasis, which may lead to discovery of therapeutic vulnerabilities in TNBC. To identify the novel regulator that controls HIF activity, we screened 720 epigenetic regulators and found that SAP30 is induced by HIF-1 and HIF-2, and in turn interacts with the alpha subunit of HIF-1 and HIF-2 to enhances their target gene expression in TNBC cells. SAP30 is highly and selectively expressed in human TNBC, and high levels of SAP30 are positively correlated with poor survival of these patients. Genetic deletion of SAP30 blocks TNBC growth and lung metastasis in xenograft mice. These exciting results suggest that SAP30 may act on HIFs-mediated gene dysregulation to promote TNBC progression and metastasis. The central goal of the current R01 project is to dissect the detailed mechanisms by which SAP30 increases HIF activation and TNBC progression and metastasis. Three Specific Aims are proposed to address this goal. In Aim 1, we will define the underlying mechanism of SAP30 upregulation in TNBC by using human TNBC cell lines and tissues. In Aim 2, we will decipher the regulatory mechanism of SAP30-mediated HIF activation in TNBC. In Aim 3, we will dissect the molecular mechanisms of SAP30-dependent TNBC growth and metastasis using SAP30 knockout mice we generated as well as human TNBC xenograft mice. The goal will be achieved with great support from our outstanding collaborators on campus at UT Southwestern. The successful completion of this project will provide new insights into the fundamental molecular mechanism underlying TNBC progression and metastasis, and may uncover SAP30 as a therapeutic vulnerability in TNBC.

肿瘤转移导致三阴性乳腺癌（TNBC）患者的高死亡率，但其潜在的危险因素

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

CHD4 Promotes Breast Cancer Progression as a Coactivator of Hypoxia-Inducible Factors.

DOI：
10.1158/0008-5472.can-20-1049
发表时间：
2020-09-15
期刊：
Cancer research
影响因子：
11.2
作者：
Wang Y;Chen Y;Bao L;Zhang B;Wang JE;Kumar A;Xing C;Wang Y;Luo W
通讯作者：
Luo W

Multifaceted role of branched-chain amino acid metabolism in cancer.

DOI：
10.1038/s41388-020-01480-z
发表时间：
2020-10
期刊：
Oncogene
影响因子：
8
作者：
Peng H;Wang Y;Luo W
通讯作者：
Luo W

GPT2 Is Induced by Hypoxia-Inducible Factor (HIF)-2 and Promotes Glioblastoma Growth.

DOI：
10.3390/cells11162597
发表时间：
2022-08-20
期刊：
CELLS
影响因子：
6
作者：
Zhang, Bo;Chen, Yan;Bao, Lei;Luo, Weibo
通讯作者：
Luo, Weibo

Emerging role of PARP-1 and PARthanatos in ischemic stroke.

DOI：
10.1111/jnc.15464
发表时间：
2022-01
期刊：
Journal of neurochemistry
影响因子：
4.7
作者：
Liu S;Luo W;Wang Y
通讯作者：
Wang Y

MIF is a 3' flap nuclease that facilitates DNA replication and promotes tumor growth.

DOI：
10.1038/s41467-021-23264-z
发表时间：
2021-05-19
期刊：
Nature communications
影响因子：
16.6
作者：
Wang Y;Chen Y;Wang C;Yang M;Wang Y;Bao L;Wang JE;Kim B;Chan KY;Xu W;Capota E;Ortega J;Nijhawan D;Li GM;Luo W;Wang Y
通讯作者：
Wang Y