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

Abstract

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-α (ERα) and repressed the transactivation of ERα in breast cancer cells. Mechanistically, the interaction between CHES1 and ERα enhanced the recruitment of nicotinamide adenine dinucleotide (NAD+) deacetylase Sirtuin 1 (SIRT1), and it further induced SIRT1-mediated ERα deacetylation and repression on the promoter-binding enrichment of ERα. In addition, we also found that the expression of CHES1 was repressed by estrogen-ERα signaling and the expression level of CHES1 was significantly downregulated in ERα-positive breast cancer. The detailed mechanism was that ERα may directly bind to CHES1 potential promoter via recognizing the conserved estrogen response element (ERE) motif in response to estrogen stimulation. Functionally, CHES1 inhibited ERα-mediated proliferation and tumorigenesis of breast cancer cells in vivo and in vitro. Totally, these results identified a negative cross-regulatory loop between ERα 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.

The clinical and prognostic significance of FOXN3 downregulation in acute myeloid leukaemia

“…As a tumour suppressor, the impact of FOXN3 on prognosis has been demonstrated in solid tumours. Patients with high FOXN3 expression had longer OS and RFS times than those with low FOXN3 expression in HCC, osteosarcoma and breast cancer patients . The results of this study suggested that downregulation of FOXN3 correlates with poor OS and RFS of non‐APL.…”

“…The transcription factor forkhead box N3 (FOXN3), as a member of the forkhead box N superfamily, participates in several biological processes, including the cell cycle, cell differentiation, epithelial-mesenchymal transition, gene transcription and glucose metabolism. 9-13 Previous studies have shown that the downregulated expression of FOXN3 is observed in various malignancies, such as hepatocellular carcinoma (HCC), colon cancer, ERα-positive breast cancer, Hodgkin lymphoma, head and neck cancer, lung cancer, adult glioblastoma multiforme, T cell acute lymphoblastic leukaemia (ALL)and osteosarcoma, 9,10,12,[14][15][16][17][18][19] and the FOXN3 expression level is associated with the prognosis of some cancers. Abstract Introduction: The expression of forkhead box N3 (FOXN3), also known as checkpoint suppressor 1 (CHES1), is reduced in many types of tumours.…”

“…and osteosarcoma, 9,10,12,[14][15][16][17][18][19] and the FOXN3 expression level is associated with the prognosis of some cancers. Abstract Introduction: The expression of forkhead box N3 (FOXN3), also known as checkpoint suppressor 1 (CHES1), is reduced in many types of tumours.…”

Breaking down the Contradictory Roles of Histone Deacetylase SIRT1 in Human Breast Cancer

“…A more recent study by Xu et al showed that SIRT1-mediated deacetylation of ER-α represses the transactivation of ER-α and consequently, inhibits the proliferation of BC cells in vitro. The authors showed that checkpoint suppressor 1 (CHES1) interacts with ER-α and enhances the recruitment of SIRT1, thus enabling SIRT1-mediated repression of ER-α transactivation and impairing ER-α transcriptional activity [ 74 ]. Furthermore, the SIRT1 activator resveratrol has been reported to suppress estrogen-dependent growth of luminal BC cells [ 75 ].…”

SIRT1 and Estrogen Signaling Cooperation for Breast Cancer Onset and Progression

“…On the other hand, as previously mentioned, active ERα recruits FOXO family members into transcriptomic complexes, factors which also fall under SIRT1 spectrum of actions. Within the BC context, a recent report showed FOXN3 to be able to recruit SIRT1 into ERE-dependent transcriptomic complexes, promoting reduced transcriptomic output ( 84 ). Interestingly, alterations of FOXM1 and FOXO3a levels had been previously linked to SIRT1 aberrant activity, especially in TNBC ( 85 ).…”