Category Ranking
98%
Total Visits
921
Avg Visit Duration
2 minutes
Citations
20
Article 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.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11829253 | PMC |
| http://dx.doi.org/10.1158/1078-0432.CCR-24-1166 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Risk of colorectal cancer and participation in fecal immunochemical test-based screening.
Public Health
September 2025
Department of Public Health, Erasmus MC University Medical Center, Rotterdam, the Netherlands.
Objectives: Participation rates in fecal immunochemical test (FIT)-based colorectal cancer (CRC) screening differ across socio-demographic subgroups. The largest health gains could be achieved in subgroups with low participation rates and high risk of CRC. We investigated the CRC risk within different socio-demographic subgroups with low participation in the Dutch CRC screening program.
View Article and Find Full Text PDFPrognosis of lymph node metastasis confined to lateral pelvic or mesenteric nodes in mid-low rectal cancer: multicentre retrospective cohort study.
BJS Open
September 2025
Department of Colorectal Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Background: Metastases in the lateral pelvic lymph nodes or mesenteric lymph nodes represent distinct categories of mid-low rectal cancer. This study investigated the patterns of mesenteric and lateral pelvic lymph node metastases in mid-low rectal cancer; the survival benefit of postoperative treatment was also analysed in these groups.
Methods: This retrospective multicentre study included consecutive patients with mid-low rectal cancer who underwent total mesorectal excision with lateral pelvic lymph node dissection in three Chinese institutions between 2012 and 2020.
Germline rare variants in cancer susceptibility genes and subsequent neoplasm risk after childhood cancer.
J Natl Cancer Inst
September 2025
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, Maryland, United States.
Background: Among childhood cancer survivors, germline rare variants in autosomal dominant cancer susceptibility genes (AD CSGs) could increase subsequent neoplasm (SNs) risks, but risks for rarer SNs and by age at onset are not well understood.
Methods: We pooled the Childhood Cancer Survivor Study and St Jude Lifetime Cohort (median follow-up = 29.7 years, range 7.
A Remote Time-Restricted Eating and Mindfulness Intervention Addressing Risk Factors Associated with Early-Onset Colorectal Cancer Demonstrates Feasibility and Acceptability among Young Adults: A Randomized Controlled Pilot Trial.
Nutr Cancer
September 2025
Department of Kinesiology and Nutrition, University of Illinois Chicago, Iowa City, IL, USA.
Increased adiposity and chronic psychosocial stress (CPS) are plausible modifiable contributors of the recent increase in early-onset colorectal cancer (EOCRC). We conducted an 8-week randomized controlled pilot trial evaluating the feasibility and acceptability of time restricted eating (TRE) (daily ad libitum eating between 12-8pm) and Mindfulness ("Mindfulness for Beginners" course from the Calm app) among young adults. Participants were randomized to the following groups: TRE ( = 10); Mindfulness ( = 11); TRE & Mindfulness ( = 11); or Control ( = 11).
View Article and Find Full Text PDFBroad-Spectrum Antibiotic Use at the End of Life in Patients With Advanced Cancer.
JAMA Netw Open
September 2025
Department of Internal Medicine, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, South Korea.
Importance: Patients with advanced cancer frequently receive broad-spectrum antibiotics, but changing use patterns across the end-of-life trajectory remain poorly understood.
Objective: To describe the patterns of broad-spectrum antibiotic use across defined end-of-life intervals in patients with advanced cancer.
Design, Setting, And Participants: This nationwide, population-based, retrospective cohort study used data from the South Korean National Health Insurance Service database to examine broad-spectrum antibiotic use among patients with advanced cancer who died between July 1, 2002, and December 31, 2021.