Characterization of the SUMO ligase PIAS1 in tumor progression and metastasis

描述（由申请人提供）：异常细胞信号传导是癌症发展和进展的主要驱动力。活化的STAT-1蛋白抑制剂（PIAS 1）通过在靶蛋白上添加小的泛素样修饰物（SUMO-链）而在细胞信号传导中起重要作用。我们的实验室最近发现PIAS 1 SUOMOylates早幼粒细胞白血病（PML）肿瘤抑制因子。该事件促进了泛素介导的PML降解，有助于肿瘤存活。例如，在非小细胞肺癌（NSCLC）和乳腺癌细胞系中使用shRNA的PIAS 1消耗导致PML水平增加，随后对凋亡和受损的细胞增殖敏感。此外，我的初步数据显示PIAS 1在NIH 3 T3和小鼠胚胎成纤维细胞（MEFs）中的过表达减少了细胞间的接触抑制。此外，癌细胞中PIAS 1的siRNA缺失干扰了细胞增殖。 在伤口愈合试验中扩散和迁移失败。值得注意的是，皮亚斯家族成员最近被牵连在细胞骨架动力学。例如，PIAS 3 SUMO化的GT3 RAC 1增加了迁移细胞中的板足形成。此外，在细胞应激条件下，粘着斑激酶（FAK）的PIAS 1 SUMO化促进了细胞活力的增加。总之，这些观察结果提出了PIAS 1可能通过在细胞应激期间增强肿瘤存活而参与肿瘤进展以及通过调节细胞形状（可能通过RAC/RHO和FAK蛋白）促进细胞迁移的假设。该提案旨在使用肺癌的细胞和小鼠模型评估PIAS 1对癌细胞存活及其转移能力的影响。这项工作有望提供一个框架，以了解SUMO化如何促进肿瘤发生。

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.