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。激活的STAT-1蛋白抑制因子(PIAS1)通过在靶蛋白上添加小的泛素样修饰物(SUMO链)，在细胞信号转导中发挥重要作用。我们的实验室最近发现PIAS1能抑制早幼粒细胞白血病(PML)的肿瘤生长。这一事件促进了泛素介导的PML的降解，有助于肿瘤生存。例如，在非小细胞肺癌(NSCLC)和乳腺癌细胞系中，使用shRNA去除PIAS1会导致PML水平增加，进而导致细胞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)中过表达可以减少细胞间接触抑制。此外，癌细胞中PIAS1的siRNA缺失会干扰细胞 伤口愈合试验中的扩散和迁移失败。值得注意的是，PIAS家族成员最近被牵连到细胞骨架动力学中。例如，GTP酶RAC1的PIAS3 SUMO化增加了迁移细胞中板足的形成。此外，在细胞应激条件下，粘着斑激酶(FAK)的PIAS1 SUMO化促进了细胞存活率的增加。综上所述，这些观察结果提出了一种假设，即PIAS1可能通过在细胞应激期间提高肿瘤存活率，并通过调节细胞形状促进细胞迁移，可能通过Rac/Rho和FAK蛋白参与肿瘤进展。这项建议旨在利用肺癌的细胞和小鼠模型来评估PIAS1对癌细胞存活和转移能力的影响。这项工作有望为理解SUMO化如何促进肿瘤发生提供一个框架。

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.