Serine-Phosphorylated STAT3 Promotes Tumorigenesis via Modulation of RNA Polymerase Transcriptional Activity
Serine-Phosphorylated STAT3 Promotes Tumorigenesis via Modulation of RNA Polymerase Transcriptional Activity
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DOI：
10.1158/0008-5472.can-19-0974
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发表时间：
2019-10-15
期刊：
影响因子：
11.2
通讯作者：
Jenkins, Brendan J.
中科院分区：
文献类型：
--
作者：
Balic, Jesse J.;Garama, Daniel J.;Jenkins, Brendan J.
在包括胃癌在内的许多人类上皮恶性肿瘤中，潜在致癌转录因子STAT3的失调控激活总是与其典型酪氨酸磷酸化和增强的转录活性相关。相比之下，STAT3的丝氨酸磷酸化（pS）可以增强其核转录活性并促进必要的线粒体功能，但pS-STAT3在上皮性癌症中的作用尚不明确。在gp130（F/F）自发性胃癌小鼠模型和人胃癌细胞系异种移植物中，我们发现基因消融pS-STAT3可以抑制肿瘤生长，同时降低肿瘤上皮的增殖潜力。微阵列基因表达谱显示，ps - stat3缺失的gp130(F/)F小鼠的胃肿瘤发生受到抑制，与stat3调控的基因网络的转录活性降低有关，这些基因网络涉及细胞增殖和迁移、炎症和血管生成，但与线粒体功能或代谢无关。值得注意的是，pS-STAT3的致瘤活性与其主要增强RNA聚合酶ii介导的转录延伸的能力一致，而不是STAT3靶基因的起始。此外，通过基于内源蛋白快速免疫沉淀质谱（RIME）测定的体外和体内蛋白质组学组合方法，我们确定了ruvb样AAA atp酶1 （RUVBL1/Pontin）和基本同源增强子（ERH）是pS-STAT3的相互作用伙伴，它们对STAT3靶基因的转录活性至关重要。总的来说，这些发现揭示了pS-STAT3在胃癌中迄今未知的转录作用和专性需求，这可以推断为其他stat3驱动的癌症。意义：这些发现揭示了胃癌中组成型STAT3丝氨酸磷酸化的新的转录作用和强制性要求。
Deregulated activation of the latent oncogenic transcription factor STAT3 in many human epithelial malignancies, including gastric cancer, has invariably been associated with its canonical tyrosine phosphorylation and enhanced transcriptional activity. By contrast, serine phosphorylation (pS) of STAT3 can augment its nuclear transcriptional activity and promote essential mitochondrial functions, yet the role of pS-STAT3 among epithelial cancers is ill-defined. Here, we reveal that genetic ablation of pS-STAT3 in the gp130(F/F) spontaneous gastric cancer mouse model and human gastric cancer cell line xenografts abrogated tumor growth that coincided with reduced proliferative potential of the tumor epithelium. Microarray gene expression profiling demonstrated that the suppressed gastric tumorigenesis in pS-STAT3-deficient gp130(F/)F mice associated with reduced transcriptional activity of STAT3-regulated gene networks implicated in cell proliferation and migration, inflammation, and angiogenesis, but not mitochondrial function or metabolism. Notably, the protumorigenic activity of pS-STAT3 aligned with its capacity to primarily augment RNA polymerase II-mediated transcriptional elongation, but not initiation, of STAT3 target genes. Furthermore, by using a combinatorial in vitro and in vivo proteomics approach based on the rapid immunoprecipitation mass spectrometry of endogenous protein (RIME) assay, we identified RuvB-like AAA ATPase 1 (RUVBL1/Pontin) and enhancer of rudimentary homolog (ERH) as interacting partners of pS-STAT3 that are pivotal for its transcriptional activity on STAT3 target genes. Collectively, these findings uncover a hitherto unknown transcriptional role and obligate requirement for pS-STAT3 in gastric cancer that could be extrapolated to other STAT3-driven cancers.Significance: These findings reveal a new transcriptional role and mandatory requirement for constitutive STAT3 serine phosphorylation in gastric cancer.