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MECHANISM BY WHICH MBD2 INHIBITORS SUPPRESS COLORECTAL CANCER PROGRESSION VIA EPIGENETIC REPRESSION OF ONCOGENIC WNT16 ACTIVATION

Tingting Luo 1, Yuting Liu 1, Jiahui Lin 1, Tian Tian 1, Jian Qi 1

Affiliations

1 The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, China

Summary

AI Generated

Pharmacological inhibition of methyl-CpG-binding domain protein 2 (MBD2) reduces colorectal cancer tumor burden in patient-derived xenograft models by downregulating WNT16 oncogene expression without inducing genomic instability.

MBD2 inhibitor treatment downregulated WNT16 expression at RNA and protein levels and suppressed Wnt/β-catenin signaling in colorectal cancer cells that exhibited hypomethylation at the WNT16 promoter with diminished MBD2 occupancy
In patient-derived xenograft models, MBD2 inhibition reduced tumor burden without inducing genomic instability, which is a hallmark toxicity of conventional DNA methyltransferase inhibitors
The study employed clinical specimens, cell lines, patient-derived organoids, and PDX models with whole-genome bisulfite sequencing, RNA-seq, chromatin immunoprecipitation sequencing, and CRISPR interference
The authors propose that MBD2-targeted therapy achieves precise correction of carcinogenic epigenetic lesions while avoiding genome-wide hypomethylation risks associated with broad-spectrum DNA methyltransferase inhibitors
This work is relevant to researchers and clinicians investigating targeted epigenetic therapies for colorectal cancer

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Abstract

Introduction

Colorectal cancer, the third most prevalent malignancy globally[1], exhibits strong associations with aberrant DNA methylation patterning. While DNA methyltransferase inhibitors (DNMTis) demonstrate therapeutic efficacy in hematologic malignancies, their clinical application in solid tumors remains constrained by dose-limiting genomic instability secondary to genome-wide hypomethylation[2]. Recent mechanistic studies have established methyl-CpG-binding domain protein 2 (MBD2) as a pivotal mediator of methylation-dependent transcriptional repression; however, its potential involvement in context-dependent oncogene activation remains unresolved. This study elucidates that pharmacological MBD2 inhibition achieves dual epigenetic rectification – reactivating tumor suppressor genes through promoter demethylation while selectively attenuating WNT16 overexpression via methylation-sensitive suppression, thereby establishing a targeted therapeutic paradigm that circumvents the pleiotropic toxicity associated with conventional DNMTis.

Aims & Methods

A multi-dimensional platform encompassing clinical specimens, cell lines, patient-derived organoids, and PDX models was employed. Integrative whole-genome bisulfite sequencing and RNA-seq analyses delineated methylation-driven transcriptional networks. Chromatin immunoprecipitation sequencing characterized MBD2 binding at differentially methylated regions, with CRISPR interference validating functional regulatory elements.

Results

CRC cells exhibited pronounced hypomethylation at the WNT16 promoter accompanied by diminished MBD2 occupancy. MBD2 inhibitor treatment downregulated WNT16 expression at both RNA and protein levels, concomitant with suppression of Wnt/β-catenin signaling. In PDX models, MBD2 inhibition reduced tumor burden without inducing genomic instability—a hallmark toxicity of conventional DNMTis.

Conclusion

This study unveils a novel epigenetic mechanism wherein MBD2 facilitates oncogenic WNT16 activation via its "methylation reader" function. Compared to broad-spectrum DNMTis, MBD2-targeted therapy achieves precise correction of carcinogenic epigenetic lesions while avoiding genome-wide hypomethylation risks, advancing a paradigm for targeted CRC treatment.

References

[1] Jiexi Li, Xingdi Ma, Deepavali Chakravarti, Shabnam Shalapour, Ronald A DePinho. Genetic and biological hallmarks of colorectal cancer. Genes Dev.
2021;35(11-12):787-820
[2] Marie Lopez, Julie Gilbert, Jean Contreras, Ludovic Halby, Paola B Arimondo. Inhibitors of DNA Methylation. Adv Exp Med Biol. 2022;1389:471-513
[3] Yang Xie, Feng Wang, Jun Yu, Jing Zhang, Yuting Liu, Mengying Li, Jian Qi. Silencing of MBD2 and EZH2 inhibits the proliferation of colorectal carcinoma cells by rescuing the expression of SFRP. Oncol Rep. 2021;46(6):250.

Conference

UEG Week Berlin 2025

Topics

Colorectal

Submission format

Abstract

Session

Colorectal cancer: Back to basics (Posters)

Citation

United European Gastroenterology Journal 2025; 13 (Supplement 8)

Published

2025

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EFFECTS OF GAMMA-AMINOBUTYRIC ACID SUPPLEMENTATION ON SYMPTOMS AND QUALITY OF LIFE IN IBS-D PATIENTS. PRELIMINARY RESULTS FROM A RANDOMIZED, DOUBLE BLINDED, PLACEBO CONTROLLED, CROSSOVER STUDY

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