C-Terminal Binding Protein: A Molecular Link between Metabolic Imbalance and Epigenetic Regulation in Breast Cancer

Abstract

The prevalence of obesity has given rise to significant global concerns as numerous population-based studies demonstrate an incontrovertible association between obesity and breast cancer. Mechanisms proposed to account for this linkage include exaggerated levels of carbohydrate substrates, elevated levels of circulating mitogenic hormones, and inflammatory cytokines that impinge on epithelial programming in many tissues. Moreover, recently many scientists have rediscovered the observation, first described by Otto Warburg nearly a century ago, that most cancer cells undergo a dramatic metabolic shift in energy utilization and expenditure that fuels and supports the cellular expansion associated with malignant proliferation. This shift in substrate oxidation comes at the cost of sharp changes in the levels of the high energy intermediate, nicotinamide adenine dinucleotide (NADH). In this review, we discuss a novel example of how shifts in the concentration and flux of substrates metabolized and generated during carbohydrate metabolism represent components of a signaling network that can influence epigenetic regulatory events in the nucleus. We refer to this regulatory process as “metabolic transduction” and describe how the C-terminal binding protein (CtBP) family of NADH-dependent nuclear regulators represents a primary example of how cellular metabolic status can influence epigenetic control of cellular function and fate.

Inhibition of C-terminal binding protein attenuates transcription factor 4 signaling to selectively target colon cancer stem cells

“…[12][13][14]17,42 In earlier investigations, its role in transcriptional repression was highlighted. 17 However, accumulating evidence suggest that its role in transcriptional activation is just as important in mediating its oncogenic activities.…”

“…14,24 Moreover, CtBP was shown to regulate expression of breast CSC markers. 15 Hence, we hypothesized that CtBP, a redox regulated transcriptional modulator, which is frequently overexpressed in colorectal cancer 16 will regulate colonic CSC growth and self-renewal.…”

“…Given the importance of cellular redox potential in governing CSCs growth and self-renewal, it is highly probable that CtBP plays a role in regulation of CSC phenotype. 8,14 In fact, in an in vitro model of estrogen receptor responsive and triple negative breast cancer, CtBP knockdown resulted in attenuation of CD44/CD24 ratio suggestive of inhibition of CSC phenotype. 15 Increasing evidence points to a tumor promoter role for CtBP in various cancers including colorectal cancer.…”

C-terminal binding proteins: central players in development and disease

“…Indeed, CtBP1 has been found to localize to ribbon synapses in sensory neurons, where it is thought to provide structure to synaptic ribbons (38,39). In addition, CtBP1-S, more commonly known as CtBP/BARS, is known to participate in the process of membrane trafficking and Golgi partitioning during mitosis (25,26) as well as regulate membrane composition in cancer cells (40). In addition to CtBP1, the CtBP2 gene also produces two splice variants of CtBP2 known as CtBP2-L and CtBP2-S, as well as a third isoform known as RIBEYE, which functions predominantly in the cytoplasm at ribbon synapses and has been extensively characterized in sensory neurons and bipolar cells (37,(41)(42)(43).…”

“…More recently, a genome-wide analysis was performed to provide a more comprehensive description of CtBP repression targets. From this study, CtBP targets could be categorized into three main categories: genes that regulate cell renewal and pluripotency, genes that regulate genome stability, and genes that regulate epithelial differentiation and prevent epithelial-to-mesenchymal transition (EMT) (40,106). Remarkably, these three classes also describe pathways that are classically dysregulated in cancer.…”