Checkpoint suppressor 1 suppresses transcriptional activity of ERα and breast cancer cell proliferation via deacetylase SIRT1

Breast cancer is a highly heterogeneous carcinoma in women worldwide, but the underlying mechanisms that account for breast cancer initiation and development have not been fully established. Mounting evidence indicates that Checkpoint suppressor 1 (CHES1) is tightly associated with tumorigenesis and prognosis in many types of cancer. However, the definitive function of CHES1 in breast cancer remains to be explored. Here we showed that CHES1 had a physical interaction with estrogen receptor-alpha (ER alpha) and repressed the transactivation of ER alpha in breast cancer cells. Mechanistically, the interaction between CHES1 and ER alpha enhanced the recruitment of nicotinamide adenine dinucleotide (NAD+) deacetylase Sirtuin 1 (SIRT1), and it further induced SIRT1-mediated ER alpha deacetylation and repression on the promoter-binding enrichment of ER alpha. In addition, we also found that the expression of CHES1 was repressed by estrogen-ER alpha signaling and the expression level of CHES1 was significantly downregulated in ER alpha-positive breast cancer. The detailed mechanism was that ER alpha may directly bind to CHES1 potential promoter via recognizing the conserved estrogen response element (ERE) motif in response to estrogen stimulation. Functionally, CHES1 inhibited ER alpha-mediated proliferation and tumorigenesis of breast cancer cells in vivo and in vitro. Totally, these results identified a negative cross-regulatory loop between ER alpha and CHES1 that was required for growth of breast cancer cells, it might uncover novel insight into molecular mechanism of CHES1 involved in breast cancer and provide new avenues for molecular-targeted therapy in hormone-regulated breast cancer.