A hyperactive splice variant of STAT3 promotes colonic inflammation-associated tumorigenesis in mice

Signal transducer and activator of transcription 3 (STAT3) is essential for cell signaling in response to extracellular stimuli, and its overactivation is a hallmark of inflammation and tumorigenesis. The differential mechanisms underlying the physiological and pathological regulation of STAT3 remain elusive. Here we demonstrate that cryptic splice sites in STAT3 generate heterogeneous isoforms with or without a single amino acid S701 (wS701/?S701), with the latter being substantially upregulated in colon cancers. Intrinsic S701 undergoes reversible phosphorylation catalyzed by mTOR complex 1 (mTORC1) and protein phosphatase 2A (PP2A). Upon inflammatory stimulation, precursor phosphorylation at S701 sequesters Y705 phosphorylation by interfering with the access of janus kinase 1/2 (JAK1/2), and restricts STAT3 overactivation. In contrast, the ?S701 isoform is hyperactive due to absence of this self-restricting mechanism. Deletion of S701 in mice increases susceptibility to colonic inflammation and tumorigenesis. Pharmacological inhibition of PP2A sustains S701 phosphorylation, and alleviates colon inflammation in wild-type but not in ?S701 mice. Our findings highlight the importance of STAT3 heterogeneity in human diseases. Overall design: To investigate function of Stat3_?S701 isoform in DSS-induced IBD in mice, we established ?S701 mice. We then treated WT and ?S701 mice with DSS for 3 days and collected their colons. Total RNA was extracted from the colon of WT and ?S701 mice after 3-day DSS treatment using TRNzol Universal reagent and then subjected to RNA-seq.