Abstract 2043: Deregulated Cdc7/Dbf4 expression promotes DNA repair and checkpoint recovery to enhance survival and associates with poor prognosis in OSCC

Cdc7 (DDK, Dbf4-dependent kinase) is a serine-threonine kinase and required to initiate DNA replication from each origin. Although Cdc7 and Dbf4 has been shown overexpressed in many human cancer cell lines and certain primary tumors, only few cancer tissue samples were analyzed. In this report, in light of the biological, prognostic, and therapeutic implications of Cdc7 in tumorigenesis, we investigated and found that Cdc7 is overexpressed specifically in malignant non-small-cell lung cancer (NSCLC), colorectal cancer and oral squamous cell carcinoma (OSCC) tissues and Cdc7 expression level is an independent prognosis factor for patient survival in OSCC. Cdc7 is required for DNA replication and higher Cdc7 level is linked to the development of tumor cells, however, increased Cdc7 expression levels do not always correlate with the proliferative status of the tumor cells. Therefore, the underlying mechanism of overexpressed Cdc7/Dbf4 in promoting tumorigenesis still needs to be clarified. Our data suggest that up-regulation of Cdc7 has several roles in promoting tumorigenesis. First, overexpression of Cdc7 promotes cell survival through inhibiting DNA damage-induced cell apoptosis and inducing HR DNA repair. Second, during the early stage, it causes checkpoint activation as well as slow-down of S phase progression and promotes HR DNA repair that may through DSB-mediated mechanism. Third, during the late stage, upon removal of DNA lesions and completion of DNA repair in S-phase, Cdc7 attenuates checkpoint signaling and reactivates DNA replication by promoting the loading of replication initiation proteins Cdc45 as well as the activation of Plk1, which will be important for checkpoint recovery and replication restart. In summary, we have shown that a highly significant association between Cdc7 expression and overall survival in OSCC patient, rendering the prognostic importance and clinical practicability of Cdc7 expression in OSCC. Our studies also indicate that increased Cdc7 expression promotes HR repair and attenuates ATM/ATR checkpoint signaling for recovery of damaged replication forks to enhance the survival of DNA damaging agent-treated tumor cells. These studies will open an avenue to the biological, prognostic, and therapeutic applications of Cdc7 kinase in cancer therapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2043. doi:1538-7445.AM2012-2043