Steroid Receptor Coactivator 1 is an Integrator of Glucose and NAD+/NADH Homeostasis

Abstract

Steroid receptor coactivator 1 (SRC-1) drives diverse gene expression programs necessary for the dynamic regulation of cancer metastasis, inflammation and gluconeogenesis, pointing to its overlapping roles as an oncoprotein and integrator of cell metabolic programs. Nutrient utilization has been intensely studied with regard to cellular adaptation in both cancer and noncancerous cells. Nonproliferating cells consume glucose through the citric acid cycle to generate NADH to fuel ATP generation via mitochondrial oxidative phosphorylation. In contrast, cancer cells undergo metabolic reprogramming to support rapid proliferation. To generate lipids, nucleotides, and proteins necessary for cell division, most tumors switch from oxidative phosphorylation to glycolysis, a phenomenon known as the Warburg Effect. Because SRC-1 is a key coactivator responsible for driving a hepatic gluconeogenic program under fasting conditions, we asked whether SRC-1 responds to alterations in nutrient availability to allow for adaptive metabolism. Here we show SRC-1 is stabilized by the 26S proteasome in the absence of glucose. RNA profiling was used to examine the effects of SRC-1 perturbation on gene expression in the absence or presence of glucose, revealing that SRC-1 affects the expression of complex I of the mitochondrial electron transport chain, a set of enzymes responsible for the conversion of NADH to NAD(+). NAD(+) and NADH were subsequently identified as metabolites that underlie SRC-1's response to glucose deprivation. Knockdown of SRC-1 in glycolytic cancer cells abrogated their ability to grow in the absence of glucose consistent with SRC-1's role in promoting cellular adaptation to reduced glucose availability.

Steroid receptor coactivators: servants and masters for control of systems metabolism

“…Under fasting conditions, hepatic SRC-1 expression is upregulated and induces gluconeogenesis by coactivating CEBPα and increasing transcription of its target gene pyruvate carboxylase ( PC ) [26]. Administering either glucose or insulin, both of which represent carbohydrate signaling molecules, decreases SRC-1 expression, whereas glucose deprivation increases SRC-1 protein stability by reducing its 26S proteasomal degradation via altered NAD + /NADH ratios, metabolites that underlie SRC-1's response to glucose deprivation [26,27]. …”

“…The activation of AMPK enhances SRC-2 transcriptional activity to drive BSEP gene expression to promote energy accretion [20]. In the case of SRC-1, both its activity and stability are responsive to fluctuations in glucose levels leading to the selective expression of complex I components of the mitochondrial electron transport chain, which facilitates the conversion of NADH to NAD + [27]. The elevated NAD + pool, in turn, enhances SRC-1 stability to improve the glucose-deprived cellular state.…”

“…Moving forward, defining SRC actions in these tissues will be crucial to understanding their overall roles in coordinating systems metabolism. Additionally, available data suggest that expression of SRC family members can be adjusted is response to dietary cues and changes in the metabolic state, but the mechanistic underpinnings that explain these events remain largely unexplored [13,26,27]. Moreover, few studies focus on tissue-specific sensors or upstream metabolic regulators for SRC activation or repression.…”

Use of RNA-seq to identify cardiac genes and gene pathways differentially expressed between dogs with and without dilated cardiomyopathy

“…39 Steroid receptor coactivator 1, the protein generated by NCOA1 , is also important in glucose homeostasis and cellular energy production. 40 Taken together, downregulation of these genes points to severe cellular energy dysregulation in dogs with DCM.…”

Transcriptional coregulators: emerging roles of SRC family of coactivators in disease pathology

“…2008), and its expression is an important predictor of time-to-disease relapse (Dasgupta, et al 2012b). Recent studies have identified coactivators such as SRC-1, SRC-3 and PGC-1α as regulators of bioenergetic pathways in cancer cells (Motamed, et al 2014, Vazquez, et al 2013, Zhao, et al 2014). PGC-1α promotes mitochondrial oxidative phosphorylation to generate sufficient energy supporting the anabolic needs of tumor cells.…”