YAP–IL-6ST autoregulatory loop activated on APC loss controls colonic tumorigenesis

Significance Current therapy for advanced colorectal cancer (CRC) is unsatisfactory and CRC remains a major cause of cancer-related deaths. Thus, novel and ubiquitously acting oncogenic mediators that are amenable to pharmacological targeting need to be identified. We found that loss of adenomatous polyposis coli (APC), which is mutated in the majority of human CRC, results in up-regulation of the signaling protein IL-6ST/gp130. This results in activation of Src family kinases (SFKs), YAP, Notch, and STAT3, which are simultaneously activated in 64% of human CRC. In addition to better explaining how APC loss initiates colorectal tumorigenesis, we show that combined treatment with SFK and JAK inhibitors results in regression of established colorectal tumors in mice. Loss of tumor suppressor adenomatous polyposis coli (APC) activates β-catenin to initiate colorectal tumorigenesis. However, β-catenin (CTNNB1) activating mutations rarely occur in human colorectal cancer (CRC). We found that APC loss also results in up-regulation of IL-6 signal transducer (IL-6ST/gp130), thereby activating Src family kinases (SFKs), YAP, and STAT3, which are simultaneously up-regulated in the majority of human CRC. Although, initial YAP activation, which stimulates IL6ST gene transcription, may be caused by reduced serine phosphorylation, sustained YAP activation depends on tyrosine phosphorylation by SFKs, whose inhibition, along with STAT3-activating JAK kinases, causes regression of established colorectal tumors. These results explain why APC loss is a more potent initiating event than the mere activation of CTNNB1.