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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metabolism

Background:

• The c-Myc protooncogene drives glucose metabolism for biosynthesis.
• c-Myc upregulates glucose transporters and glycolytic enzymes while downregulating TXNIP, a glucose uptake inhibitor.
• A Mychigh/TXNIPlow signature predicts poor prognosis in triple-negative breast cancer (TNBC).

Purpose of the Study:

• To investigate the role of TXNIP in TNBC aggressiveness.
• To understand how TXNIP loss influences c-Myc's genomic binding and transcriptional activity.

Main Methods:

• Generation of TXNIP null MDA-MB-231 (231:TKO) cells.
• Analysis of transcriptional programs and global c-Myc genome occupancy in 231:TKO cells compared to parental cells.

Main Results:

• TXNIP loss induced a transcriptional program similar to c-Myc.
• TXNIP deficiency increased global c-Myc genome occupancy, enabling binding to new promoters and enhancers.
• This expanded c-Myc binding and transcription occurred without altering c-Myc levels or intrinsic activity.

Conclusions:

• TXNIP acts as a broad repressor of c-Myc genomic binding.
• TXNIP loss mimics c-Myc overexpression by increasing c-Myc's access to its genomic targets.
• These findings connect c-Myc activity to nutrient-sensing pathways regulating TXNIP expression in TNBC.