TY  - JOUR
A1  - Ulreich, Katharina
A1  - Firnau, May-Britt
A1  - Tagscherer, Nina
A1  - Beyer, Sandra
A1  - Ackermann, Anne
A1  - Plotz, Guido
A1  - Brieger, Angela
T1  - 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
T2  - Cancers
N2  - 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.
KW  - casein kinase 2
KW  - CK2α
KW  - MLH1
KW  - DNA mismatch repair
KW  - phosphorylation
KW  - colorectal cancer
Y1  - 2022
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/81936
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-819365
SN  - 2072-6694
N1  - This work was supported by the Wilhelm Sander Foundation (2015.161.2) and did not receive any funding from a commercial company.
N1  - Data supporting already reported CK2α promotor SNPs are available under https://www.genecards.org, accessed on 1 January 2022.
VL  - 14
IS  - 6, art. 1553
SP  - 1
EP  - 20
PB  - MDPI
CY  - Basel
ER  -