Transcription factor Sp1 is upregulated by PKCι to drive the expression of YAP1 during pancreatic carcinogenesis

Abstract

Recently, we identified that the atypical protein kinase C isoform ι (PKCι) enhances the expression of 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 PKCι 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 PKCι, Sp1 and YAP1 is correlated and associated with the stages and prognosis of pancreatic tumors. Moreover, our apoptotic detection data demonstrate that combination of PKCι and Sp1 inhibitors at subtoxic doses displays synergistic effects on inducing apoptosis and reversing the immunosuppression of pancreatic cancer cells, establishing the combination of PKCι 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.

Paired protein kinases PRKCI-RIPK2 promote pancreatic cancer growth and metastasis via enhancing NF-κB/JNK/ERK phosphorylation

“…The oncogenic role of PRKCI-encoding protein PKC iota has been well established, recent studies in PC suggested that mutated KRAS can elevate and activate PKC iota to disable growth-inhibitory Hippo signaling and promote Yes-associated protein1 (YAP-1) translocation into nucleus, and thus maintain PC cells growth (Wang et al 2020 ). Also, PKC iota upregulates transcription factor specificity protein 1 to promote transactivation of YAP-1 and induce tumorigenesis (Yang et al 2021 ). In turn, the produced YAP-1 can be recruited by PKC iota to increase PD-L1 expression, resulting in immune evasion under the microenvironment of PC (Zhang et al 2021c ).…”

Protein Kinase C (PKC) Isozymes as Diagnostic and Prognostic Biomarkers and Therapeutic Targets for Cancer

“…These changes promote the growth of pancreatic cancer [ 248 ]. Inhibition of PKCι alone [ 249 ] or in combination with other inhibitors (e.g., specificity protein 1 (Sp1) inhibitor) [ 250 ] reduced cell growth and metastasis and induced apoptosis in pancreatic cancer cells. These studies suggest that PKCι can be a promising therapeutic target for pancreatic cancer.…”

Highlights on the Role of KRAS Mutations in Reshaping the Microenvironment of Pancreatic Adenocarcinoma

“…The expression and function of proliferative Yes-associated protein (YAP1) have shown to be upregulated in KRAS mutated PDAC through the atypical protein kinase C isoform ι (PKCι), leading to the progression of PDAC, reprogramming of microenvironment, and immune invasion of PDAC [ 98 ]. PKCι has been shown to upregulate another important protein called Specificity protein 1 (Sp1).…”

“…This protein is the first identified member of the Sp/XKLF (specificity protein/Krüppel-like factor) family of transcription factors shown to modulate apoptosis, differentiation, angiogenesis, and growth of many different cell types [ 99 ]. It has been reported that upregulated Sp1via PKC1 can bind to multiple sites of YAP1 promoter driving its transcription, which ultimately leads to upregulation of PDl-1 and thus the proliferation of PDAC as well as cytotoxic immune response resistance [ 98 ]. The induction of apoptosis and reversion of the immunosuppression of pancreatic cancer cells was accomplished through the combination of PKCι and Sp1 inhibitors at sub-toxic doses.…”

“…The synergistic effect of this combination has been shown to sensitize PDAC to the cytotoxicity of natural killer (NK) cells. Interestingly, significant suppression of PDL1 expression in PDAC was also achieved through this combination therapy [ 98 ].…”