Faculty, Staff and Student Publications

Publication Date

11-15-2024

Journal

Clinical Cancer Research

DOI

10.1158/1078-0432.CCR-24-1166

PMID

39269307

PMCID

PMC11829253

PubMedCentral® Posted Date

5-15-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

Purpose: BRAFV600E-mutated colorectal cancer exhibits a strong correlation with DNA hypermethylation, suggesting that this subgroup of tumors presents unique epigenomic phenotypes. Nonetheless, 5-azacitidine, which inhibits DNA methyltransferase activity, is not efficacious in BRAFV600E colorectal cancer in vivo.

Experimental design: We randomized and treated mice implanted with patient-derived tumor xenografts harboring BRAFV600E mutation with control, 5-azacitidine, vemurafenib (BRAF inhibitor), or the combination. Comprehensive epigenomic profiling was conducted on control and 5-azacitidine-treated tumor samples, including DNA methylation, histone modifications, chromatin accessibility, and gene expression. Combinations of epigenetic agents were explored in preclinical BRAFV600E colorectal cancer models.

Results: A profound reduction of DNA methylation levels upon 5-azacitidine treatment was confirmed, however, transcriptional repression was not relieved. This study unbiasedly explored the adaptive engagement of other epigenomic modifications upon 5-azacitidine treatment. A loss of histone acetylation and a gain of histone methylations, including H3K27 and H3K4 trimethylation, were observed around these hypomethylated regions, suggesting the involvement of polycomb repressive complex (PRC) activity around the genome with loss of DNA methylation, therefore maintaining the repression of key tumor-suppressor genes. Combined inhibition of PRC activity through EZH2 inhibition with 5-azacitidine treatment additively improved efficacies in BRAFV600E colorectal cancer cells.

Conclusions: In conclusion, DNA hypomethylation by 5-azacitidine exhibits a close association with H3K27me3 and PRC activity in BRAFV600E colorectal cancer, and simultaneous blockade of DNA methyltransferase and EZH2 holds promise as a potential therapeutic strategy for patients with BRAFV600E-mutated colorectal cancer.

Keywords

Proto-Oncogene Proteins B-raf, Humans, Colorectal Neoplasms, Animals, DNA Methylation, Mice, Histones, Mutation, Xenograft Model Antitumor Assays, Drug Resistance, Neoplasm, Epigenesis, Genetic, Cell Line, Tumor, Epigenome, Gene Expression Regulation, Neoplastic, Azacitidine, Vemurafenib

Published Open-Access

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