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.