Prognostic Value of Polycomb Proteins EZH2, BMI1 and SUZ12 and Histone Modification H3K27me3 in Colorectal Cancer

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.

Clinical Implications of Intestinal Stem Cell Markers in Colorectal Cancer

“…46,47 However, high BMI1 expression is also correlated with a better prognosis compared to patients with low expression. 48 By combing several biomarkers with the BMI1 expression, prognostic stratification is improved. 48 In addition, another recent study reported that patients with decreased postoperative plasma mRNA levels of BMI1 compared to patients with increased postoperative mRNA levels correlated with a favorable prognosis in CRC.…”

“…48 By combing several biomarkers with the BMI1 expression, prognostic stratification is improved. 48 In addition, another recent study reported that patients with decreased postoperative plasma mRNA levels of BMI1 compared to patients with increased postoperative mRNA levels correlated with a favorable prognosis in CRC. 49 These studies suggest that BMI1 may be of relevance as a prognostic indicator in CRC.…”

“…Another strategy in trying to improve the prognostic and predictive value could be to combine several of the stem cell markers in a panel rather than using only one stem cell marker, as is seen in other studies focusing on other genes and proteins. 48,109 Furthermore, adjusting for known predictive and prognostic factors, such as MMR deficiency, are necessary to further clarify the significance of the stem markers as prognostic and predictive biomarkers.…”

EZH2 promotes metabolic reprogramming in glioblastomas through epigenetic repression of EAF2-HIF1α signaling

“…Enhancer of zeste homology 2 (EZH2) is the catalytic subunit of polycomb repressive complex 2, which represses gene expression by generating a methylated epigenetic mark at Lys27 of histone H3 (H3K27me3) [7, 8]. It appears that EZH2 is up-regulated in a variety of human malignancies, including breast, colorectal, prostate, cervical and lung cancers, as well as sarcoma and glioblastoma, where its expression is associated with cancer initiation, progression, metastasis and prognosis [9, 10].…”

B-cell-specific Moloney murine leukemia virus integration site 1: potential stratification factor and therapeutic target for epithelial ovarian cancer

“…In breast cancer, overexpression of BMI1 was reported to have different influences on patient prognosis by Pietersen et al and BMI1 was found to have no prognostic value in urothelial carcinoma of the bladder 45,48. In contrast, survival data from Benard et al also showed that high expression of BMI1 was associated with better patient survival and longer recurrence-free periods, compared to prostate cancer patients with low BMI1 expression 10. Single-institution-based research with limited sample sizes might account for these inconsistent findings, while tissue/organ specificity of oncogenetic BMI1 activation needs further investigation as a priority.…”