Abstract
To investigate the roles of the homeodomain-interacting protein kinase (HIPK) family of proteins in pancreatic cancer prognosis and the possible molecular mechanism. The expression of HIPK family genes and their roles in pancreatic cancer prognosis were analysed by using The Cancer Genome Atlas (TCGA). The roles of HIPK2 in pancreatic cancer proliferation and glycolysis were tested by overexpression of HIPK2 in pancreatic cancer cells, followed by cell proliferation assay, glucose uptake analysis and Seahorse extracellular flux analysis. The mechanism of action of HIPK2 in pancreatic cancer proliferation and glycolysis was explored by examining its effect on the ERK/cMyc axis. Decreased HIPK2 expression indicated worse prognosis of pancreatic cancer. Overexpression of HIPK2 in pancreatic cancer cells decreased cell proliferation and attenuated aerobic glycolysis, which sustained proliferation of cancer cells. HIPK2 decreased cMyc protein levels and expression of cMyc-targeted glycolytic genes. cMyc was a mediator that regulated HIPK2-induced decrease in aerobic glycolysis. HIPK2 regulated cMyc protein stability via ERK activation, which phosphorylated and controlled cMyc protein stability. HIPK2 suppressed proliferation of pancreatic cancer in part through inhibiting the ERK/cMyc axis and related aerobic glycolysis.
Highlights
Pancreatic cancer is a malignant disease, and the death rate is almost equal to the incidence of the disease
We demonstrated that patients with lower HIPK2 expression exhibited worse prognosis, and lower HIPK2 correlated with worse overall survival (OS) and disease‐free sur‐ vival (DFS) (Figure 1A,B)
It is well known that enhanced aerobic glycolysis promotes uncon‐ trolled proliferation of cancer cells; we investigated whether HIPK2 negatively regulated aerobic glycolysis
Summary
Pancreatic cancer is a malignant disease, and the death rate is almost equal to the incidence of the disease. HIPKs mediate key signalling pathways that regulating the response to various stress signals, including DNA damage, reactive oxygen species and hypoxia.[6] HIPK2 is the best‐ studied member of the HIPK family and is involved in the regulation of differentiation, proliferation and apoptosis of cells.[7,8,9] In cancer, HIPK2 is generally considered to be a potential tumour suppressor as it can promote apoptosis by phosphorylating tumour suppressor protein p53, leading to expression of proapoptotic genes.[10,11] HIPK2 induces apoptosis by modulating molecules independently of p53, such as phosphorylation‐dependent degradation of antiapop‐ totic transcriptional co‐repressor CtBP.[12,13,14] Due to the structural similarities between HIPK1 and HIPK2, these two proteins share some redundant activities, and HIPK1 regulates apoptosis via in‐ teracting with nuclear proteins.[15,16] HIPK3 has been reported to reg‐ ulate the pathogenesis of type 2 diabetes.[17] To date, little is known about the roles of HIPK4 except for its capacity to phosphorylate p53 at Ser9.18 These reports demonstrate that HIPK proteins might have important roles in cancer and are promising anticancer targets. This work might provide novel predictive and treatment targets for pancreatic cancer
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