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

• 批准号: 10311065
• 负责人: Weibo Luo
• 金额: $ 37.06万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-12-01 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10311065
• 关键词: Address; BRCA1 gene; Binding; Bioinformatics; Breast Cancer Cell; Breast Cancer Model; Breast Cancer Patient; Breast Cancer cell line; 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; Knock-out; Knockout Mice; Lead; 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; 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

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 机制仍然未知。新兴研究表明基因转录失调介导TNBC 恶性肿瘤和肿瘤微环境是基因失调的关键调节因子之一。缺氧诱导 HIF-1和HIF-2是低氧应答的主要转录调节因子， 肿瘤微环境的共同特征，并激活其下游靶基因来调节许多 癌症生物学中的关键过程，包括血管生成，细胞外基质重塑，细胞迁移/侵袭， 导致TNBC进展和转移。因此，了解HIF转录的基本调控 活性将揭示TNBC进展和转移的机制，这可能会导致发现TNBC， TNBC的治疗弱点。为了鉴定控制HIF活性的新型调节因子，我们筛选了720个 表观遗传调节因子，并发现SAP 30是由HIF-1和HIF-2诱导，并反过来与α-干扰素相互作用。 HIF-1和HIF-2亚基的表达，以增强它们在TNBC细胞中的靶基因表达。SAP 30具有很高的 SAP 30在人TNBC中选择性表达，高水平的SAP 30与TNBC患者的存活率低呈正相关。 这些病人。SAP 30的遗传缺失阻断异种移植小鼠中的TNBC生长和肺转移。这些 令人兴奋的结果表明，SAP 30可能作用于HIF介导的基因失调，以促进TNBC进展 和转移。当前R 01项目的中心目标是剖析 SAP 30增加HIF活化和TNBC进展和转移。提出了三个具体目标， 实现这一目标。在目的1中，我们将通过使用以下方法来定义TNBC中SAP 30上调的潜在机制： 人TNBC细胞系和组织。目的2：阐明SAP 30介导的细胞凋亡调控机制。 TNBC中的HIF活化。在目标3中，我们将剖析SAP 30依赖性TNBC生长的分子机制 使用我们产生的SAP 30敲除小鼠以及人TNBC异种移植小鼠来观察肿瘤和转移。目标 将在德克萨斯大学西南分校校园杰出合作者的大力支持下实现。的 该项目的成功完成将为基本分子机制提供新的见解 SAP 30可能是TNBC进展和转移的潜在原因，并且可能揭示SAP 30作为TNBC中的治疗弱点。