Salt-inducible kinase 2 confers radioresistance in colorectal cancer by facilitating homologous recombination repair.

ABSTRACT: Resistance to radiotherapy remains a critical barrier in treating colorectal cancer (CRC), particularly in cases of locally advanced rectal cancer (LARC). To identify key kinases involved in CRC radioresistance, we employed a kinase-targeted CRISPR-Cas9 library screen. This approach aimed to identify potential kinase inhibitors as radiosensitizers. Our screening identified salt-inducible kinase 2 (SIK2) as a critical factor in CRC radioresistance. Increased SIK2 expression correlated with reduced tumor regression and poorer outcomes in LARC patients undergoing neoadjuvant chemoradiotherapy. The depletion of SIK2 significantly enhanced radiation-induced apoptosis and tumor regression. Mechanistically, SIK2 interacts with valosin-containing protein (VCP), promoting its hyperphosphorylation.

SUBMITTER: Meng Y 

PROVIDER: S-EPMC11774237 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature