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

Abstract

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 demonstrated that cryptic splice sites in <i>STAT3</i> generated heterogeneous isoforms with or without a single amino acid Ser701 (wS701/ΔS701), with the latter being more abundant in colon cancers. Intrinsic S701 underwent reversible phosphorylation catalyzed by mechanistic target of rapamycin complex 1 (mTORC1) and protein phosphatase 2A (PP2A). Upon inflammatory stimulation, phosphorylation at S701 (p-S701) sequestered Y705 phosphorylation (p-Y705) by interfering with the access of Janus kinase 1/2 and restricting STAT3 overactivation. In contrast, the STAT3_ΔS701 isoform was hyperactive because of the absence of this self-restricting mechanism. Deletion of S701 in mice increased susceptibility to colonic inflammation and tumorigenesis. Pharmacological inhibition of PP2A sustained p-S701 and alleviated colon inflammation in wild-type but not in ΔS701 mice. Our findings highlight the importance of STAT3 heterogeneity in colonic inflammation and colorectal cancer.