SIRT1 represses estrogen-signaling, ligand-independent ERα-mediated transcription, and cell proliferation in estrogen-responsive breast cells

Abstract

In prostate and breast cancer, the androgen and estrogen receptors mediate induction of androgen- and estrogen-responsive genes respectively, and stimulate cell proliferation in response to the binding of their cognate steroid hormones. Sirtuin 1 (SIRT1) is a nicotinamide adenosine dinucleotide (NAD+)-dependent class III histone deacetylase (HDAC) that has been linked to gene silencing, control of the cell cycle, apoptosis and energy homeostasis. In prostate cancer, SIRT1 is required for androgen-antagonist-mediated transcriptional repression and growth suppression of prostate cancer cells. Whether SIRT1 plays a similar role in the actions of estrogen or antagonists had not been determined. We report here that SIRT1 represses the transcriptional and proliferative response of breast cancer cells to estrogens, and this repression is estrogen receptor-alpha (ERα)-dependent. Inhibition of SIRT1 activity results in the phosphorylation of ERα in an AKT-dependent manner, and this activation requires phosphoinositide 3-kinase (PI3K) activity. Phosphorylated ERα subsequently accumulates in the nucleus, where ERα binds DNA ER-response elements and activates transcription of estrogen-responsive genes. This ER-dependent transcriptional activation augments estrogen-induced signaling, but also activates ER-signaling in the absence of estrogen, thus defining a novel and unexpected mechanism of ligand-independent ERα-mediated activation and target gene transcription. Like ligand-dependent activation of ERα, SIRT1 inhibition-mediated ERα activation in the absence of estrogen also results in breast cancer cell proliferation. Together, these data demonstrate that SIRT1 regulates the most important cell signaling pathway for the growth of breast cancer cells, both in the presence and the absence of estrogen.

Female headstart in resistance to hyperoxia-induced oxidative stress in mice.

“…Sirt1 has been found to repress PPAR-γ activity thus promoting fat mobilization (Picard et al, 2004), and attenuate cellular oxidative stress toxicity through induction of Sod2 expression (Tanno et al, 2010). Upregulated Sirt1 along with decreased PPAR-γ triggers reduction of fat storage, a primary way by which calorie restriction extends lifespan in mammals (Picard et al, 2004), and those data are in accordance with our results showing female mice better coping with oxidative stress since a role of Sirt1 in cell-dependency upon estrogen has been shown (Moore & Faller, 2013). PPAR-γ plays an important role in adipogenesis, and as such has been implicated in the pathology of numerous diseases including diabetes, atherosclerosis and cancer (Mansure et al, 2009).…”

CITED2 modulates estrogen receptor transcriptional activity in breast cancer cells

“…A potentially key interaction is that with Cbp-p300, a known binding partner of CITED2 having documented ability to interact with the A/B domain of ER, thereby increasing its ligand-independent activity [25]. Also of interest is the effect of CITED2 on ER phosphorylation at serine 104/106/118 , reported to influence the interaction of co-activators with the A/B domain of ER [25], as well as any effect on known repressors of ligand-independent ER transcription such as the histone deacetylase SIRT1 [26]. Such studies will not only further our understanding of ligand-independent ER activation, but may contribute toward the advancement of breast cancer prognostication and treatment.…”

The SIRT 3 Expression Profile is Associated with Pathological and Clinical Outcomes in Human Breast Cancer Patients

“…SIRT1 regulates dishevelled proteins and promotes transient and constitutive Wnt signaling in several cancer cell lines including breast cancer cells [15]. SIRT1 represses estrogen-signaling, ligand-independent estrogen α-mediated transcription and cell proliferation in estrogen-responsive breast cells [16]. SIRT1 is essential for oncogenic signaling by estrogen/estrogen receptor α in breast cancer [17].…”