In:
PLOS Biology, Public Library of Science (PLoS), Vol. 21, No. 3 ( 2023-3-17), p. e3001778-
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 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.
Type of Medium:
Online Resource
ISSN:
1545-7885
DOI:
10.1371/journal.pbio.3001778
DOI:
10.1371/journal.pbio.3001778.g001
DOI:
10.1371/journal.pbio.3001778.g002
DOI:
10.1371/journal.pbio.3001778.g003
DOI:
10.1371/journal.pbio.3001778.g004
DOI:
10.1371/journal.pbio.3001778.g005
DOI:
10.1371/journal.pbio.3001778.g006
DOI:
10.1371/journal.pbio.3001778.g007
DOI:
10.1371/journal.pbio.3001778.t001
DOI:
10.1371/journal.pbio.3001778.s001
DOI:
10.1371/journal.pbio.3001778.s002
DOI:
10.1371/journal.pbio.3001778.s003
DOI:
10.1371/journal.pbio.3001778.s004
DOI:
10.1371/journal.pbio.3001778.s005
DOI:
10.1371/journal.pbio.3001778.s006
DOI:
10.1371/journal.pbio.3001778.s007
DOI:
10.1371/journal.pbio.3001778.s008
DOI:
10.1371/journal.pbio.3001778.s009
DOI:
10.1371/journal.pbio.3001778.s010
DOI:
10.1371/journal.pbio.3001778.s011
DOI:
10.1371/journal.pbio.3001778.s012
DOI:
10.1371/journal.pbio.3001778.s013
DOI:
10.1371/journal.pbio.3001778.s014
DOI:
10.1371/journal.pbio.3001778.r001
DOI:
10.1371/journal.pbio.3001778.r002
DOI:
10.1371/journal.pbio.3001778.r003
DOI:
10.1371/journal.pbio.3001778.r004
DOI:
10.1371/journal.pbio.3001778.r005
DOI:
10.1371/journal.pbio.3001778.r006
Language:
English
Publisher:
Public Library of Science (PLoS)
Publication Date:
2023
detail.hit.zdb_id:
2126773-X
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