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

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 (CK2 alpha) causes phosphorylation of the MMR protein MLH1 at position serine 477, which significantly inhibits the MMR. In the present study, CK2 alpha-dependent MLH1 phosphorylation was analyzed in vivo. Using a cohort of 165 patients, we identified 88 CRCs showing significantly increased nuclear/cytoplasmic CK2 alpha expression, 28 tumors with high nuclear CK2 alpha expression and 49 cases showing a general low CK2 alpha expression. Patients with high nuclear/cytoplasmic CK2 alpha expression demonstrated significantly reduced 5-year survival outcome. By immunoprecipitation and Western blot analysis, we showed that high nuclear/cytoplasmic CK2 alpha expression significantly correlates with increased MLH1 phosphorylation and enriched somatic tumor mutation rates. The CK2 alpha mRNA levels tended to be enhanced in high nuclear/cytoplasmic and high nuclear CK2 alpha-expressing tumors. Furthermore, we identified various SNPs in the promotor region of CK2 alpha, which might cause differential CK2 alpha expression. In summary, we demonstrated that high nuclear/cytoplasmic CK2 alpha 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.

Automated summary

High nuclear/cytoplasmic expression of CK2 alpha in colorectal cancer correlates with enhanced MLH1 phosphorylation and may cause increased mutation rates. These findings suggest important new therapeutic targets.