Characterization of the SUMO ligase PIAS1 in tumor progression and metastasis

描述（申请人提供）：异常细胞信号是癌症发生和发展的主要驱动力。活化STAT-1蛋白抑制剂（PIAS1）通过在靶蛋白上添加小泛素样修饰物（sumo -链），在细胞信号传导中起着重要作用。我们的实验室最近发现PIAS1 suomoylate早幼粒细胞白血病（PML）肿瘤抑制因子。这一事件促进泛素介导的PML降解，帮助肿瘤存活。例如，在非小细胞肺癌（NSCLC）和乳腺癌细胞系中使用shRNA耗尽PIAS1可导致PML水平升高，随后易发生凋亡和细胞增殖受损。此外，我的初步数据显示，PIAS1在NIH3T3和小鼠胚胎成纤维细胞（mef）中的过表达降低了细胞间接触抑制。此外，癌细胞中PIAS1的siRNA缺失会干扰细胞

DESCRIPTION (provided by applicant): Aberrant cell signaling is the main driving force in the development and progression of cancer. Protein inhibitor of activated STAT-1 (PIAS1) plays a fundamental role in cellular signaling by adding small ubiquitin like modifiers (SUMO-chains) onto target proteins. Our lab recently discovered that PIAS1 SUOMOylates the promyelocytic leukemia (PML) tumor suppressor. This event promotes the ubiquitin-mediated degradation of PML, aiding tumor survival. For example, PIAS1 depletion using shRNA in non-small cell lung cancer (NSCLC) and breast cancer cell lines leads to increased PML levels, followed susceptibility to apoptosis and impaired cell proliferation. In addition, my preliminary data show that PIAS1 overexpression in NIH3T3 and mouse embryonic fibroblasts (MEFs) reduces cell-to-cell contact inhibition. Furthermore, siRNA depletion of PIAS1 in cancer cells interferes with cell spreading and failure to migrate in wound healing assays. Notably, PIAS family members have recently been implicated in cytoskeleton dynamics. For instance, PIAS3 SUMOylation of the GTPase RAC1 increased lamelipodia formation in migrating cells. Moreover, PIAS1 SUMOylation of focal adhesion kinase (FAK) promoted increased cell viability under conditions of cellular stress. Together, these observations raise the hypothesis that PIAS1 may be implicated in tumor progression by potentiating tumor survival during cellular stress and in the promotion of cell migration by modulating cell shape, potentially through RAC/RHO and FAK proteins. This proposal aims to evaluate the impact of PIAS1 on the survival of cancer cells and their ability to metastasize using cellular and mouse models of lung cancer. This work is expected to provide a framework to understand how SUMOylation promotes tumorigenesis.