HIPK2 Cooperates with KRAS Signaling and Associates with Colorectal Cancer Progression

Homeodomain-interacting protein kinase 2 (HIPK2) is an evolutionary conserved kinase that has gained attention as a fine tuner of multiple signaling pathways, among which those commonly altered in colorectal cancer. The aim of this study was to evaluate the relationship of HIPK2 expression with progression markers and mutational pattern and gain insights into the contri-bution of HIPK2 activity in colorectal cancer. We evaluated a retrospective cohort of colorectal cancer samples by IHC for HIPK2 expression and by next-generation sequencing (NGS) for the detection of mutations of cancer associated genes. We show that the percentage of HIPK2-positive cells increases with tumor pro-gression, significantly correlates with tumor-node-metastasis (TNM) staging and associates with a worse outcome. In addition, we observed that high HIPK2 expression significantly associates with KRAS mutations but not with other cancer-related genes. Functional characterization of the link between HIPK2 and KRAS show that activation of the RAS pathway either due to KRAS mutation or via upstream receptor stimulation, increases HIPK2 expression at the protein level. Of note, HIPK2 physically partici-pates in the active RAS complex while HIPK2 depletion impairs ERK phosphorylation and the growth of tumors derived from KRAS mutated colorectal cancer cells. Overall, this study identifies HIPK2 as a prognostic biomarker candidate in patients with colorectal cancer and underscores a previously unknown functional link between HIPK2 and the KRAS signaling pathway.

Automated summary

This study investigated the expression of HIPK2 in colorectal cancer and its association with disease progression and mutational patterns. The results showed that the percentage of HIPK2-positive cells increased with tumor progression and was significantly correlated with tumor-stage and poorer prognosis. Additionally, high HIPK2 expression was found to be significantly associated with KRAS mutations but not with other cancer-related genes. Functional analysis revealed that activation of the RAS pathway, either through KRAS mutation or upstream receptor stimulation, increased HIPK2 expression. Depletion of HIPK2 impaired ERK phosphorylation and tumor growth in colorectal cancer cells with KRAS mutations.