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

Abstract

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 Mychigh/TXNIPlow 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.

D-mannose alleviates intervertebral disc degeneration through glutamine metabolism

“…Lim et al [ 23 ] discovered that TXNIP loss increases MYC-dependent gene expression by increasing Myc genome occupancy in several types of cells rather than by directly affecting MYC protein expression. Consistent with the findings of Lim et al [ 23 ], it was observed that knocking down Txnip in NP cells did not significantly alter the expression of MYC (Fig. 5 g; Additional file 1 : Fig.…”

“…MYC directly promotes the cellular uptake of glutamine by increasing the transcription of SLC1A5 (the main glutamine transporter) through the enhancer box (E-box, CACGTG) [ 26 ]. Intriguingly, Lim et al [ 23 ] reported that MYC-dependent genes affected by TXNIP loss are highly and significantly enriched for canonical CACGTG MYC-binding E-boxes. Our transcriptomic analysis also revealed a significant upregulation of Slc1a5 expression in response to mannose (Fig.…”

“…In this study, focus was placed on Myc , the primary gene of interest, and found that mannose does not affect MYC protein expression but directly influences the levels of SLC1A5 and intracellular glutamine. Lim et al [ 23 ] reported that knocking down Txnip does not affect MYC protein levels but that intracellular Txnip knockdown can increase MYC genomic binding in various cell types. Therefore, it is believed that mannose upregulates the Txnip gene, which reduces MYC genomic binding, leading to the downregulation of SLC1A5 and consequently affecting intracellular glutamine levels.…”

Rewired Metabolism Caused by the Oncogenic Deregulation of MYC as an Attractive Therapeutic Target in Cancers

“…At the same time, metabolic stress activates metabolic sensors, such as MondoA, which is able to reduce glucose uptake and aerobic glycolysis via induction of thioredoxin-interacting protein (TXNIP) [ 135 , 136 ]. TXNIP activation decreases the genome occupancy of MYC, thereby inhibiting its transactivating function [ 137 ]. However, the functional relationship between MYC and MondoA is tumor type-specific and influenced by altered MYC levels.…”