Transcription Factor Sp1 Is Upregulated By Pkc Iota To Drive The Expression Of Yap1 During Pancreatic Carcinogenesis

Recently, we identified that the atypical protein kinase C isoform iota (PKC iota) enhances the expression of Yes-associated protein 1 (YAP1) to promote the tumorigenesis of pancreatic adenocarcinoma harboring mutant KRAS (mu-KRAS). To advance our understanding about underlying mechanisms, we analyze the transcription of YAP1 in pancreatic cancer cells and reveal that transcription factor specificity protein 1 (Sp1) is upregulated by PKC iota and subsequently binds to multiple sites in YAP1 promoter to drive the transactivation of YAP1 in pancreatic cancer cells carrying mu-KRAS. The bioinformatics analysis further substantiates that the expression of PKC iota, Sp1 and YAP1 is correlated and associated with the stages and prognosis of pancreatic tumors. Moreover, our apoptotic detection data demonstrate that combination of PKC iota and Sp1 inhibitors at subtoxic doses displays synergistic effects on inducing apoptosis and reversing the immunosuppression of pancreatic cancer cells, establishing the combination of PKC iota and Sp1 inhibitors as a promising novel therapeutic approach, or an adjuvant strategy to potentiate the antitumor effects of other immunotherapeutic agents in pancreatic cancer treatment.