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

Abstract

c-Myc protooncogene places a demand on glucose uptake to drive glucose-dependent biosynthetic pathways. To achieve this demand, c-Myc protein (Myc henceforth) drives the expression of glucose transporters 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. To better understand how TXNIP function contributes to the aggressive behavior of TNBC, we generated TXNIP null MDA-MB-231 (231:TKO) cells for our study. We show here 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 metabolic signals that control TXNIP expression.

Amino acid deprivation induces TXNIP expression by NRF2 downregulation

“…5,28 Recently, several studies have shown that dysregulation of TXNIP expression plays an important role in the progression of several tumors and correlates with poor clinical outcomes. 5,6 However, the role of TXNIP in the metabolism of AA remains unclear. In this study, we investigated the effects of individual AA deprivation on TXNIP expression in NSCLC cells.…”

“…TXNIP has been recognized as a metabolic protein involved in maintaining glucose homeostasis and regulating glucose metabolism 5,28 . Recently, several studies have shown that dysregulation of TXNIP expression plays an important role in the progression of several tumors and correlates with poor clinical outcomes 5,6 . However, the role of TXNIP in the metabolism of AA remains unclear.…”

“…Conversely, other studies have shown that TXNIP expression is suppressed in tumors compared to adjacent normal tissues. Moreover, TXNIP expression decreases with increasing tumor grade, and low TXNIP expression correlates with poor clinical outcomes in various cancers, such as hepatocarcinoma, breast cancer, and lung cancer 5,6 . TXNIP has emerged as an essential metabolic regulator of lipid and glucose metabolism 7,8 .…”

“…Moreover, TXNIP expression decreases with increasing tumor grade, and low TXNIP expression correlates with poor clinical outcomes in various cancers, such as hepatocarcinoma, breast cancer, and lung cancer. 5,6 TXNIP has emerged as an essential metabolic regulator of lipid and glucose metabolism. 7,8 TXNIP knockout mice are predisposed to death under fasting conditions due to a switch in metabolism to hyperlipidemia and hypoglycemia.…”