SIRT7-mediated deacetylation of XRCC6 at lysine 591 drives breast cancer progression

The acetylation level of XRCC6 is significantly decreased in clinical breast cancer tissues compared with paracancerous tissues; however, the relationship between this alteration and the occurrence and development of breast cancer remains unclear.

Acetylproteomics was employed to detect changes in protein acetylation levels in clinical samples. Co-immunoprecipitation (Co-IP) assays were utilized to identify the acetyltransferase and deacetylase responsible for XRCC6 K591 acetylation. Transwell chamber assays were performed to evaluate the impact of XRCC6 K591 acetylation on the invasive capability of breast cancer cells, while colony formation assays were conducted to assess its effect on clonogenicity.

EP300 was identified as the acetyltransferase responsible for catalyzing XRCC6 acetylation, while Sirt7 functions as its specific deacetylase. Downregulation of XRCC6 acetylation at K591 promotes its interaction with PARP1, thereby elevating XRCC6 PARylation levels and augmenting the DNA damage repair capacity of breast cancer cells. Furthermore, in vivo experiments demonstrated that reduced XRCC6 acetylation promotes tumor growth and increases tumor volume in xenograft models.

Our findings elucidate a novel mechanism by which downregulated XRCC6 acetylation drives breast cancer progression.