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Updated: Jun 13, 2025
Genome-Wide Analysis of DNA Methylation in Gastrointestinal Cancer
Published on: September 18, 2020
Epigenome Reprogramming Through H3K27 and H3K4 Trimethylation as a Resistance Mechanism to DNA Methylation Inhibition
Hey Min Lee1, Ajay Kumar Saw2, Van K Morris1
1Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
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.
Insights
5-azacitidine reduces DNA methylation in BRAFV600E colorectal cancer but does not relieve repression. Combining DNA methyltransferase and EZH2 inhibition shows therapeutic promise for this cancer subtype.
Area of Science:
- Oncology
- Epigenetics
- Genomics
Background:
- BRAFV600E-mutated colorectal cancer (CRC) is linked to DNA hypermethylation, indicating distinct epigenomic profiles.
- Despite this, 5-azacitidine, a DNA methyltransferase inhibitor, is ineffective in BRAFV600E CRC models in vivo.
Purpose of the Study:
- To investigate the epigenomic effects of 5-azacitidine in BRAFV600E CRC.
- To explore combination therapies involving epigenetic agents in preclinical BRAFV600E CRC models.
Main Methods:
- Mice with patient-derived BRAFV600E-mutated tumor xenografts were treated with control, 5-azacitidine, vemurafenib, or combination therapy.
- Comprehensive epigenomic profiling (DNA methylation, histone modifications, chromatin accessibility, gene expression) was performed on tumor samples.
Main Results:
- 5-azacitidine significantly reduced DNA methylation but failed to alleviate transcriptional repression.
- Treatment led to decreased histone acetylation and increased H3K27 and H3K4 trimethylation, suggesting Polycomb Repressive Complex (PRC) involvement.
- Combined inhibition of DNA methyltransferase and EZH2 (a PRC component) enhanced therapeutic efficacy in BRAFV600E CRC cells.
Conclusions:
- In BRAFV600E CRC, 5-azacitidine-induced DNA hypomethylation is associated with H3K27me3 and PRC activity.
- Simultaneous blockade of DNA methyltransferase and EZH2 presents a promising therapeutic strategy for BRAFV600E-mutated colorectal cancer.
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