Colorectal Cancer Cell Differentiation Is Dependent on the Repression of Aerobic Glycolysis by NDRG2-TXNIP Axis

Abstract

Background: Poorly differentiated colorectal cancers are more aggressive. Metabolism reprogramming is a significant hallmark in cancer, and aerobic glycolysis is common. However, how cancer cells reprogramming glucose metabolism contributes to cell differentiation was largely unknown. Previous studies have reported that tumor suppressor NDRG2 could promote colorectal cancers differentiation.

Aims: This study aims to demonstrate that NDRG2 promotes the differentiation of colorectal cancers, potentially through the inhibition of aerobic glycolysis via TXNIP induction.

Methods: Western blotting, qRT-PCR and immunohistochemical staining were used to detect the expression of related molecules. MTT assay was used to reflect cell viability and proliferation. Immunofluorescent assay was performed to identify the expression and distribution of molecules. Luciferase analysis and CHIP assays were used to investigate the mechanism. Bioinformatic analysis was performed to predict the relevance.

Results: In colorectal cancers, NDRG2 could inhibit cell proliferation, reduce glucose uptake and decrease expression of key glycolysis enzymes. Upregulated NDRG2 is associated with differentiated cancer. However, deletion of TXNIP, a classic glucose metabolism inhibitor, could obviously alter the function of NDRG2 in differentiation, glucose uptake, expression of key glycolysis enzymes and proliferation. Mechanistically, high glucose flux promotes the activity of TXNIP promoter. And NDRG2 promotes the occupancy of transcription factor Mondo A on TXNIP promoter, predominantly through the suppression of c-myc, which could complete with Mondo A binding to TXNIP promoter. In clinical samples, high expression of TXNIP indicates good prognosis and outcome.

Conclusions: NDRG2-dependent induction of TXNIP is critical for the aerobic glycolysis during colorectal cancers differentiation.

Keywords: Colorectal cancer; Differentiation; Glycolysis; NDRG2; TXNIP.