Abstract
BackgroundPost-translational modification of histone tails by methylation plays an important role in tumorigenesis. In this study, we investigated the nuclear expression of H3K4me3, H3K9me3 and H4K20me3 in early-stage colon cancer in relation to clinical outcome.MethodsTumor tissue cores of 254 TNM stage I-III colorectal cancer patients were immunohistochemically stained for H3K4me3, H3K9me3 and H4K20me3 and scored using the semi-automated Ariol system. Cox proportional hazard trend analyses were performed to assess the prognostic value of the combined markers with respect to patient survival and tumor recurrence.ResultsThe histone methylation markers only showed prognostic value in early-stage (TNM stage I and II) colon cancer. Therefore, only this patient set (n = 121) was used for further statistical analyses. Low nuclear expression of H3K4me3, and high expression of H3K9me3 and H4K20me3 were associated with good prognosis. In combined marker analyses, the patient group showing most favorable expression (low H3K4me3, high H3K9me3 and high H4K20me3) was associated with the best prognosis. Multivariate trend analyses showed significantly increased hazard ratios (HR) for each additional marker showing unfavorable expression, as compared to the “all favorable” reference group. The HR for disease-free survival was 3.81 (1.72-8.45; p = 0.001), for locoregional recurrence-free survival 2.86 (1.59-5.13; p < 0.001) and for distant recurrence-free survival 2.94 (1.66-5.22; p < 0.001).ConclusionsCombined nuclear expression of histone modifications H3K4me3, H3K9me3 and H4K20me3 is prognostic in early-stage colon cancer. The combination of expression of the three histone modifications provides better stratification of patient groups as compared to the individual markers and provides a good risk assessment for each patient group.
Highlights
Post-translational modification of histone tails by methylation plays an important role in tumorigenesis
As these three histone methylation markers have been found to contribute to the tumorigenic process in various cancers, we hypothesized that these histone modifications would correlate to clinical outcome in colon cancer
For patients with TNM stage III, no significant differences were observed for patients with either colon (p = 0.7) or rectal cancer (p = 0.6). These results indicate prognostic value of Trimethylation of lysine on histone H3 (H3K4me3), Trimethylation of lysine on histone H3 (H3K9me3) or H4K20me3 expression in early-stage colon cancer patients
Summary
Post-translational modification of histone tails by methylation plays an important role in tumorigenesis. As epigenetic mechanisms are potentially reversible, they represent suitable targets for the development of new anti-cancer therapies Both DNA methylation and histone modifications might present as possible new biomarkers in cancer. Epigenetic regulation of gene expression through posttranslational modification of histone proteins by methylation plays an important role in many biological processes, including cell-cycle regulation, DNA damage- and stress response, embryonic development and cellular differentiation [2]. Marión et al showed that loss of H4K20me contributed to telomere reprogramming and a higher tumorigenic potential [10] As these three histone methylation markers have been found to contribute to the tumorigenic process in various cancers, we hypothesized that these histone modifications would correlate to clinical outcome in colon cancer
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