Estrogen related receptor β mediated regulation of SIRT1  in breast cancer progression

Abstract

Silent mating type information regulation 2 homolog 1 (SIRT1) is an NAD+ dependent class III histone deacetylase (HDAC) which plays a vital role in cell survival, senescence and metabolism. SIRT1 is overexpressed in several cancers, including breast cancer. Due to the lack of endocrine therapy for ER-ve breast cancers, it is essential to identify the molecular targets having therapeutic importance. SIRT1 is a known target gene of estrogen receptor α (ERα) and well associated with ERα deacetylation. Transcription factor Estrogen related receptors (ERRs) share sequence homology with ERs in DNA binding domain, therefore possibility of sharing target genes between them is high. Our present study aim to elucidate the role of ERRβ in the regulation of SIRT1 in breast cancer tumorigenesis. SIRT1 was highly up-regulated in ER + ve breast cancer cells and tissues. Analysis of 5’ upstream region of SIRT1 suggested the presence of six putative ERRE sites and in-vitro and in-vivo studies confirmed the binding of ERRβ to them. We found SIRT1 to be up-regulated in ERRβ overexpressed ER + ve breast cancer cells. Furthermore, our results suggested the up-regulation of SIRT1 upon ectopic expression of ERRβ along with PCAF. We also proved the tumorigenic role of SIRT1 with enough evidence showing the significant role of SIRT1 in cell proliferation, migration and colony formation capacity. Collectively our results suggest the tumorigenic role of SIRT1 in the breast cancer and SIRT1 inhibitors might serve as potential therapeutic drugs for the treatment of breast cancer.