PASD1 promotes STAT3 activity and tumor growth by inhibiting TC45-mediated dephosphorylation of STAT3 in the nucleus
PASD1 promotes STAT3 activity and tumor growth by inhibiting TC45-mediated dephosphorylation of STAT3 in the nucleus
复制标题
PASD1 通过抑制细胞核中 TC45 介导的 STAT3 去磷酸化来促进 STAT3 活性和肿瘤生长
DOI：
10.1093/jmcb/mjw005
复制
发表时间：
2016
影响因子：
5.5
通讯作者：
Shu Hong-Bing
中科院分区：
文献类型：
--
作者：
Xu Zhi-Sheng;Zhang Hong-Xia;Zhang Yu-Long;Liu Tian-Tian;Ran Yong;Chen Liu-Ting;Wang Yan-Yi;Shu Hong-Bing
转录因子信号转导子和转录激活子3（STAT 3）的激活在各种生理过程（例如细胞增殖、存活和分化）中受到严格调节，并且异常的STAT 3激活导致肿瘤发生。在这项研究中，我们确定了癌症/睾丸抗原PASD 1作为STAT 3活性的正调节因子。过表达PASD 1激活STAT 3并增强IL-6诱导的STAT 3激活，而敲低PASD 1则具有相反的作用。内源性免疫共沉淀实验表明PASD 1与STAT 3在细胞核内相互作用。过表达PASD 1增强了基础和IL-6诱导的STAT 3在Y 705的磷酸化，而敲低PASD 1则具有相反的作用。PASD 1与一种核蛋白酪氨酸磷酸酶TC 45竞争结合STAT 3，从而抑制了TC 45介导的STAT 3去磷酸化。一致地，PASD 1的敲除抑制了许多原癌基因的表达，导致细胞增殖、非贴壁依赖性生长、细胞迁移和裸鼠肿瘤生长的抑制。我们的研究结果表明，PASD 1作为一个关键的核STAT 3介导的基因表达和肿瘤发生的正调控。
Activation of the transcription factor signal transducer and activator of transcription 3 (STAT3) is tightly regulated during various physiological processes, such as cell proliferation, survival, and differentiation, and aberrant STAT3 activation results in tumorigenesis. In this study, we identified the cancer/testis antigen PASD1 as a positive regulator of STAT3 activity. Overexpression of PASD1 activated STAT3 and potentiated IL-6-induced activation of STAT3, whereas knockdown of PASD1 had opposite effects. Endogenous coimmunoprecipitation experiments indicated that PASD1 interacted with STAT3 in the nucleus. Overexpression of PASD1 enhanced both basal and IL-6-induced STAT3 phosphorylation at Y705, whereas knockdown of PASD1 had opposite effects. Mechanistically, PASD1 competed with TC45, a nuclear protein tyrosine phosphatase, to associate with STAT3, thus inhibited TC45-mediated dephosphorylation of STAT3. Consistently, knockdown of PASD1 inhibited expression of many pro-oncogenic genes, leading to suppression of cell proliferation, anchorage-independent growth, cell migration, and tumor growth in nude mice. Our findings demonstrate that PASD1 serves as a critical nuclear positive regulator of STAT3-mediated gene expression and tumorigenesis.