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

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 机制仍不清楚。新出现的研究表明，基因转录失调介导了TNBC 恶性肿瘤和肿瘤微环境是基因失调的重要调节因子之一。低氧可诱导 因子(HIF)，主要是HIF-1和HIF-2，是低氧反应的主要转录调节因子，a 肿瘤微环境的共同特征，并激活其下游靶基因调控多个 肿瘤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，这可能导致发现 TNBC的治疗脆弱性。为了确定控制HIF活性的新型调控因子，我们筛选了720 表观遗传调节子，发现SAP30由HIF-1和HIF-2诱导，并反过来与阿尔法相互作用 HIF-1和HIF-2亚基，以增强其在TNBC细胞中的靶基因表达。SAP30高度和 在人TNBC中选择性表达，高水平的SAP30与预后不良呈正相关。 这些病人。SAP30基因缺失阻断了异种移植小鼠的TNBC生长和肺转移。这些 令人兴奋的结果表明，SAP30可能作用于HIFs介导的基因失调，促进TNBC进展 和转移。当前R01项目的中心目标是剖析通过以下方式实现的详细机制 SAP30增加HIF的激活和TNBC的进展和转移。提出了三个具体目标来 实现这一目标。在目标1中，我们将定义SAP30在TNBC中上调的潜在机制，方法是使用 人TNBC细胞系和组织。在目标2中，我们将破译SAP30介导的调控机制 缺氧诱导因子在TNBC中的激活。在目标3中，我们将剖析SAP30依赖的TNBC生长的分子机制 使用我们建立的SAP30基因敲除小鼠和人TNBC异种移植小鼠进行研究和转移。目标是 在德克萨斯大学西南分校杰出的合作伙伴的大力支持下，我们将实现这一目标。这个 这个项目的成功完成将为我们提供对基本分子机制的新见解。 潜在的TNBC进展和转移，并可能揭示SAP30作为TNBC的治疗漏洞。

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.