Altered polymerase theta expression promotes chromosomal instability in salivary adenoid cystic carcinoma

Genomic instability (GIN) plays a key role in cancer progression. The disorders of polymerase theta (POLQ) were reported to contribute to GIN and progression in many cancers. Here, we found that POLQ over-expression was related to salivary adenoid cystic carcinoma (SACC) progression and poor prognosis. Then, we investigated the role and mechanism of POLQ in the GIN in SACC. GIN was assessed by chromosome staining with DAPI and Giemsa, as well as qRT-PCR of the mitosis-related gene expression. Meanwhile, PCR-SSCP was used to evaluate microsatellite instability. Modulation of POLQ expression increased chromosomal instability and enhanced the sensitivity to etoposide without impacting microsatellite stability. Mechanistically, POLQ regulated genome stability by promoting the expression of the error-prone alt-NHEJ-related protein PARP1, and down-regulating c-NHEJ- and HR-related proteins KU70 and RAD51. In vitro CCK, Transwell assays and in vivo murine xenograft models indicated that the PARP inhibitor olaparib suppressed SACC growth in the case of etoposide-induced DNA damage. Bioinformatic analysis identified CEBPB as a potential POLQ-regulating transcription factor. In summary, our research provides new insights into the mechanisms of SACC chromosomal instability and identifies new potential targets for SACC treatment.

Automated summary

Research has found that overexpression of polymerase theta (POLQ) is related to the progression and poor prognosis of salivary adenoid cystic carcinoma (SACC). POLQ plays a role in increasing chromosomal instability and enhancing sensitivity to etoposide. This is achieved by promoting the expression of error-prone alt-NHEJ-related protein PARP1 and downregulating c-NHEJ- and HR-related proteins KU70 and RAD51. The PARP inhibitor olaparib has been shown to suppress SACC growth in the presence of etoposide-induced DNA damage.