Journal Article

TXNIP loss expands Myc-dependent transcriptional programs by increasing Myc genomic binding

Varley, Katherine E., Murphy, Kristin E., Thomas, Mallory L., Vahrenkamp, Jeffery M., Wilde, Blake R., Conway, Megan E., Ayer, Donald E., Lim, Tian-Yeh, Gertz, Jason

2023

Overview

The c-Myc protooncogene places a demand on glucose uptake to drive glucose-dependent biosynthetic pathways. To meet this demand, c-Myc protein (Myc henceforth) drives the expression of glucose transporters, glycolytic enzymes, and represses the expression of thioredoxin interacting protein (TXNIP), which is a potent negative regulator of glucose uptake. A Myc high /TXNIP low gene signature is clinically significant as it correlates with poor clinical prognosis in triple-negative breast cancer (TNBC) but not in other subtypes of breast cancer, suggesting a functional relationship between Myc and TXNIP. To better understand how TXNIP contributes to the aggressive behavior of TNBC, we generated TXNIP null MDA-MB-231 (231:TKO) cells for our study. We show that TXNIP loss drives a transcriptional program that resembles those driven by Myc and increases global Myc genome occupancy. TXNIP loss allows Myc to invade the promoters and enhancers of target genes that are potentially relevant to cell transformation. Together, these findings suggest that TXNIP is a broad repressor of Myc genomic binding. The increase in Myc genomic binding in the 231:TKO cells expands the Myc-dependent transcriptome we identified in parental MDA-MB-231 cells. This expansion of Myc-dependent transcription following TXNIP loss occurs without an apparent increase in Myc’s intrinsic capacity to activate transcription and without increasing Myc levels. Together, our findings suggest that TXNIP loss mimics Myc overexpression, connecting Myc genomic binding and transcriptional programs to the nutrient and progrowth signals that control TXNIP expression.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Analysis / Arrestins / Binding / Biological Transport / Biology and Life Sciences / Breast cancer / c-Myc protein / Carrier Proteins - genetics / Carrier Proteins - metabolism / Cell cycle / Cell division / Cell growth / Clinical outcomes / Consortia / Datasets / Enhancers / Gene expression / Genomics / Glucose / Glucose - metabolism / Glycolysis / Humans / Hypotheses / Hypothesis testing / Identification and classification / Medicine and Health Sciences / Metabolism / Myc protein / Properties / Protein expression / Proteins / Proto-Oncogene Proteins c-myc - metabolism / Taxonomy / Thioredoxin / Transcription / Transcription factors / Transcriptomes / Triple Negative Breast Neoplasms - genetics / Tumors