High Expression of Casein Kinase 2 Alpha Is Responsible for Enhanced Phosphorylation of DNA Mismatch Repair Protein MLH1 and Increased Tumor Mutation Rates in Colorectal Cancer.

Abstract

Simple SummaryColorectal cancer (CRC) is associated with DNA mismatch repair (MMR) deficiency. The serine/threonine casein kinase 2 alpha (CK2α) is able to phosphorylate and inhibit MMR protein MLH1 in vitro. This study aimed to analyze the relevance of CK2α for MLH1 phosphorylation in vivo. Around 50% of CRCs were identified to express significantly increased nuclear/cytoplasmic CK2α. High nuclear/cytoplasmic CK2α level could be significantly correlated with reduced 5-year survival outcome of patients, increased MLH1 phosphorylation, and enriched somatic tumor mutation rates. Overall, our study demonstrated, in vivo, that enhanced CK2α leads to an increase of MLH1 phosphorylation, higher tumor mutation rates, and is an unfavorable prognosis for patients.DNA mismatch repair (MMR) deficiency plays an essential role in the development of colorectal cancer (CRC). We recently demonstrated in vitro that the serine/threonine casein kinase 2 alpha (CK2α) causes phosphorylation of the MMR protein MLH1 at position serine 477, which significantly inhibits the MMR. In the present study, CK2α-dependent MLH1 phosphorylation was analyzed in vivo. Using a cohort of 165 patients, we identified 88 CRCs showing significantly increased nuclear/cytoplasmic CK2α expression, 28 tumors with high nuclear CK2α expression and 49 cases showing a general low CK2α expression. Patients with high nuclear/cytoplasmic CK2α expression demonstrated significantly reduced 5-year survival outcome. By immunoprecipitation and Western blot analysis, we showed that high nuclear/cytoplasmic CK2α expression significantly correlates with increased MLH1 phosphorylation and enriched somatic tumor mutation rates. The CK2α mRNA levels tended to be enhanced in high nuclear/cytoplasmic and high nuclear CK2α-expressing tumors. Furthermore, we identified various SNPs in the promotor region of CK2α, which might cause differential CK2α expression. In summary, we demonstrated that high nuclear/cytoplasmic CK2α expression in CRCs correlates with enhanced MLH1 phosphorylation in vivo and seems to be causative for increased mutation rates, presumably induced by reduced MMR. These observations could provide important new therapeutic targets.