Abstract
Numerous changes in epigenetic mechanisms have been described in various types of tumors. In search for new biomarkers, we investigated the expression of Polycomb-group (PcG) proteins EZH2, BMI1 and SUZ12 and associated histone modification H3K27me3 in colorectal cancer. Nuclear expression of PcG proteins and histone modification H3K27me3 were immunohistochemically (IHC) stained on a tissue microarray (TMA), including 247 tumor tissues and 47 normal tissues, and scored using the semi-automated Ariol system. Tumor tissues showed higher expression of EZH2 (p = 0.05) and H3K27me3 (p<0.001) as compared to their normal counterparts. Combined marker trend analyses indicated that an increase in the number of markers showing high expression was associated with better prognosis. High expression of all four markers in the combined marker analyses was correlated with the best patient survival and the longest recurrence-free survival, with overall survival (p = 0.01, HR 0.42(0.21–0.84)), disease-free survival (p = 0.007, HR 0.23(0.08–0.67) and local recurrence-free survival (p = 0.02, HR 0.30(0.11–0.84)). In conclusion, we found that expression of PcG proteins and H3K27me3 showed prognostic value in our study cohort. Better stratification of patients was obtained by combining the expression data of the investigated biomarkers as compared to the individual markers, underlining the importance of investigating multiple markers simultaneously.
Highlights
New prognostic biomarkers are warranted in colorectal cancer that could improve decisions for treatment of individual patients in addition to the current TNM (American Joint Committee on Cancer, AJCC [1]) staging system, as even patients with the same TNM classification present with large differences in patient survival and tumor recurrence [2,3]
We investigated the expression of three PcG proteins (EZH2, BMI1 and SUZ12) and associated histone modification H3K27me3 in colorectal cancer tissues
High Enhancer of zeste homolog 2 (EZH2) expression has been associated with poor prognosis in a series of colorectal cancer patients by Wang et al [33], whereas high EZH2 expression was found to be associated with better relapse-free survival in colon cancer patients by Fluge et al [34]
Summary
New prognostic biomarkers are warranted in colorectal cancer that could improve decisions for treatment of individual patients in addition to the current TNM (American Joint Committee on Cancer, AJCC [1]) staging system, as even patients with the same TNM classification present with large differences in patient survival and tumor recurrence [2,3]. We focused on expression of histone-modifying enzymes of the Polycomb-group (PcG) and their associated histone modification, trimethylation of lysine 27 on histone H3 (H3K27me3), in colorectal cancer tissues. Expression of BMI1 polycomb ring finger oncogene (BMI1), a component of PRC1 and an important factor in stem cells [11,12], was found to be correlated to patient outcome in several types of cancer [13,14,15,16]. SUZ12 polycomb repressive complex 2 subunit (SUZ12), another key component of the PRC2 complex, was found to have tumor-promoting functions in several cancers, including colon cancer [21,22,23]. The associated histone modification H3K27me was found to be higher expressed in tumor tissues, and to be associated with better prognosis in non-small cell lung cancer [24] and breast cancer [19]
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