Metabolic reprogramming in triple-negative breast cancer through Myc suppression of TXNIP

Abstract

Triple-negative breast cancers (TNBCs) are aggressive and lack targeted therapies. Understanding how nutrients are used in TNBCs may provide new targets for therapeutic intervention. We demonstrate that the transcription factor c-Myc drives glucose metabolism in TNBC cells but does so by a previously unappreciated mechanism that involves direct repression of thioredoxin-interacting protein (TXNIP). TXNIP is a potent negative regulator of glucose uptake, aerobic glycolysis, and glycolytic gene expression; thus its repression by c-Myc provides an alternate route to c-Myc-driven glucose metabolism. c-Myc reduces TXNIP gene expression by binding to an E-box-containing region in the TXNIP promoter, possibly competing with the related transcription factor MondoA. TXNIP suppression increases glucose uptake and drives a dependence on glycolysis. Ectopic TXNIP expression decreases glucose uptake, reduces cell proliferation, and increases apoptosis. Supporting the biological significance of the reciprocal relationship between c-Myc and TXNIP, a Myc high /TXNIP low gene signature correlates with decreased overall survival and decreased metastasis-free survival in breast cancer. The correlation between the Myc high /TXNIP low gene signature and poor clinical outcome is evident only in TNBC, not in other breast cancer subclasses. Mutation of TP53, which is a defining molecular feature of TNBC, enhances the correlation between the Myc high /TXNIP low gene signature and death from breast cancer. Because Myc drives nutrient utilization and TXNIP restricts glucose availability, we propose that the Myc high /TXNIP low gene signature coordinates nutrient utilization with nutrient availability. Further, our data suggest that loss of the p53 tumor suppressor cooperates with Myc high /TXNIP low -driven metabolic dysregulation to drive the aggressive clinical behavior of TNBC.Myc | MondoA | thioredoxin-interacting protein | glycolysis | triple-negative breast cancer

FBW7 (F-box and WD Repeat Domain-Containing 7) Negatively Regulates Glucose Metabolism by Targeting the c-Myc/TXNIP (Thioredoxin-Binding Protein) Axis in Pancreatic Cancer

“…6D). These findings suggest that c-Myc functions as a promoter of TXNIP transcription, which is consistent with observations from the study of triple-negative breast cancer (27).…”

“…Among the altered glycolysisrelated genes in the database, we selected TXNIP as the target gene and investigated whether FBW7 regulates glycolysis via TXNIP in PDAC. TXNIP has been identified as a tumor suppressor gene in various solid tumors and hematologic malignancies (27). Moreover, recent evidence indicates that TXNIP also functions as a potent negative regulator of glucose uptake and aerobic glycolysis.…”

“…Among the differentially expressed genes, FOXO1 and TXNIP are well-established regulators of glucose metabolism (26)(27)(28). Further validation using two cell lines indicated that FBW7 overexpression significantly altered TXNIP expression (Fig.…”

The glucose-sensing transcription factor MLX promotes myogenesis via myokine signaling

“…In particular, MLX has recently been shown to coordinately regulate a subset of target genes with c-Myc (Shen et al 2015) and to be necessary for survival of Myc-driven tumors . We found that c-Myc occupancy at the Txnip promoter is reciprocal to MLX and likely mediated by E-boxes contained within the CHORE motifs (Supplemental Fig.…”

Metabolic advantages and vulnerabilities in brain metastases

“…In TNBC, metabolic dysregulation is driven by factors such as glutathione S-transferase Pi 1 (GSTP1), forkhead box O 3a (FOXO3a), and EGFR-induced c-Myc (43–45). Specifically, c-Myc represses thioredoxin-interacting protein (TXNIP), an inhibitor of glycolytic gene expression and glucose uptake (46). Recent work has identified TXNIP as a suppressor of breast cancer metastasis, which strengthens the mechanistic link between metabolism and metastasis (47).…”