Mu‐KRAS attenuates Hippo signaling pathway through PKCι to sustain the growth of pancreatic cancer

The atypical protein kinase C isoform ι (PKCι) is upregulated, which cooperates with mutated KRAS (mu‐KRAS) to promote the development of pancreatic cancers. However, the exact role of PKCι in KRAS‐mediated pancreatic tumorigenesis is not fully defined. In the present study, we demonstrate that mu‐KRAS upregulates and activates PKCι, accompanied by dephosphorylation of large tumor suppressor (LATS), a key member of the growth‐inhibiting Hippo signaling pathway. As a result, Yes‐associated protein 1 (YAP1; a transcriptional coactivator) is dephosphorylated and translocates to the nucleus, which promotes transcription of downstream target genes to sustain the transformed growth of pancreatic cancer cells. In contrast, when PKCι is suppressed by the chemical inhibitor or small‐hairpin RNA, the levels of phosphorylated LATS and YAP1 are elevated and YAP1 is excluded from the nucleus, which enhances the susceptibility of pancreatic cancer cells harboring mu‐KRAS to apoptosis. These findings shed new light on the mechanisms underlying the pancreatic tumorigenesis initiated by mu‐KRAS, and suggest that the PKCι‐YAP1 signaling may potentially be therapeutically targeted for restricting the growth and inducing apoptosis in pancreatic tumors expressing mu‐KRAS. We reveal in this study that protein kinase C isoform ι (PKCι) acts as a negative regulator upstream of the Hippo signaling pathway to induce the dephosphorylation and nuclear accumulation of Yes‐associated protein 1 (YAP1), leading to an increased transcription of an array of proproliferative target genes, and the PKCι‐mediated activation of YAP1 is dependent on the cellular context of mutated KRAS in pancreatic cancer cells.