Serine-Phosphorylated STAT3 Promotes Tumorigenesis via Modulation of RNA Polymerase Transcriptional Activity.

Deregulated activation of the latent oncogenic transcription factor 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 duanyu18133 can augment its nuclear transcriptional activity and promote essential mitochondrial functions, yet the role of among epithelial cancers is ill-defined. Here, we reveal that genetic ablation of pS-duanyu18133 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 gp130^F/F mice associated with reduced transcriptional activity of gene networks implicated in cell proliferation and migration, inflammation, and angiogenesis, but not mitochondrial function or metabolism. Notably, the protumorigenic activity of pS-duanyu18133 aligned with its capacity to primarily augment RNA polymerase II-mediated transcriptional elongation, but not initiation, of duanyu18133 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-duanyu18133 that are pivotal for its transcriptional activity on duanyu18133 target genes. Collectively, these findings uncover a hitherto unknown transcriptional role and obligate requirement for pS-duanyu18133 in gastric cancer that could be extrapolated to other cancers. SIGNIFICANCE: These findings reveal a new transcriptional role and mandatory requirement for constitutive duanyu18133 serine phosphorylation in gastric cancer.

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