Colorectal Cancer Epigenetics: Complex Simplicity

VU University Amsterdam, Amsterdamo, North Holland, Netherlands
Journal of Clinical Oncology (Impact Factor: 18.43). 03/2011; 29(10):1382-91. DOI: 10.1200/JCO.2010.28.2319
Source: PubMed


Colorectal cancer (CRC) has predominantly been considered a genetic disease, characterized by sequential accumulation of genetic alterations. Growing evidence indicates that epigenetic alterations add an additional layer of complexity to the pathogenesis of CRC, and characterize a subgroup of colorectal cancers with a distinct etiology and prognosis. Epigenetic dysregulation in colorectal cancer is organized at multiple levels, involving DNA methylation, histone modifications, nucleosomal occupancy and remodeling, chromatin looping, and noncoding RNAs. Interactions between these processes and complex associations with genetic alterations have recently been unraveled. It appears that CRC epigenetics will be the paradigm for multistep carcinogenesis, as CRC genetics has been for the past three decades. This review integrates recent data on epigenetic regulation of gene expression in CRC and describes how the understanding of these processes will alter the management of CRC.

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    • "In contrast, HDACs suppress the transcription. Aberrant histone modifications not only influence gene expression and protein function but also are involved in the autophagic process (Table 2) [51]. Histone acetylation has emerged as a key regulatory mechanism for many cellular processes including autophagy. "
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    ABSTRACT: Epigenetic modifications have been considered as hallmarks of cancer and play an important role in tumor initiation and development. Epigenetic mechanisms, including DNA methylation, histone modifications, and microRNAs, may regulate cell cycle and apoptosis, as well as macroautophagy (hereafter referred to as autophagy). Autophagy, as a crucial cellular homeostatic mechanism, performs a dual role, having pro-survival or pro-death properties. A variety of signaling pathways including epigenetic control have been implicated in the upregulation or downregulation of autophagy. However, the role of epigenetic regulation in autophagy is still less well acknowledged. Recent studies have linked epigenetic control to the autophagic process. Some epigenetic modifiers are also involved in the regulation of autophagy and potentiate the efficacy of traditional therapeutics. Thus, understanding the novel functions of epigenetic control in autophagy may allow us to develop potential therapeutic approaches for cancer treatment. Copyright © 2015. Published by Elsevier Ireland Ltd.
    Cancer Letters 02/2015; 360(2). DOI:10.1016/j.canlet.2015.02.009 · 5.62 Impact Factor
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    • "The occurrence and development of colorectal cancer is a complicated multi-step process, which involves numerous factors and genes. A number of tumor-related events are involved in this process, including oncogene activation, tumor suppressor gene inactivation, mismatch repair (MMR) gene mutations and gene promoter hypermethylation (1,2). Since the identification of MMR genes, studies have investigated the association between the aberrant expression of MMR genes and hereditary nonpolyposis colorectal cancer (HNPCC) or sporadic colorectal cancer (3–5). "
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    ABSTRACT: Mismatch repair (MMR) genes play an important role in the occurrence and development of sporadic colorectal cancer; however, the effect of MMR genes on clinicopathological features and prognosis remains unclear. The aim of the present study was to observe the clinical significance of MMR gene expression in sporadic colorectal cancer. Clinicopathological data and postoperative samples from 404 patients with sporadic colorectal cancer were obtained from the Affiliated Tumor Hospital of Xinjiang Medical University. The immunohistochemistry PV-9000 two-step method was performed to measure the protein expression of human mutL homolog 1 (hMLH1), human mutS homolog (hMSH) 2, human postmeiotic segregation increased 2 (hPSM2) and hMSH6. Differences in clinicopathological features, family history and survival time subsequent to surgery between groups with normal and aberrant MMR protein (MMRP) expression were compared. A total of 27.23% of all patients showed aberrant nuclear staining of MMRP. Among the patients with aberrant MMRP expression, a higher proportion of patients showed aberrant expression of more than one type of MMRP than aberrant expression of only one type of MMRP. Aberrant expression of hMLH1/hPSM2 was most commonly observed (29/404). In addition, aberrant MMRP expression in colorectal cancer was indicated predominantly in the right hemicolon. Histological type primarily showed mucinous adenocarcinoma. In addition, with increasing body mass index (BMI), the MMRP deficiency rate was also shown to increase gradually. There was a close association between MMRP expression deficiency and family history of cancer (P<0.05). For TNM stage III patients, the Kaplan-Meier survival curve showed that the aberrant MMRP expression group had a three-year disease-free survival (DFS) rate of 66.67%, which was longer than the DFS rate of the normal group (55.41%), with no statistical difference (P>0.05). In conclusion, the immunohistochemistry PV-9000 two-step method can be used to measure MMRP expression in colorectal cancer. Aberrant MMRP expression is closely correlated with tumor location, histological type, BMI and tumor family history in sporadic colorectal cancer. Aberrant MMRP expression may have an effect on the prognosis of stage III patients.
    Experimental and therapeutic medicine 11/2014; 8(5):1416-1422. DOI:10.3892/etm.2014.1927 · 1.27 Impact Factor
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    • "Epigenetic mechanisms have been identified as factors frequently deregulated in tumors and are attractive targets for biomarker research, because of their roles in regulating gene expression and their potentially reversible nature. Numerous changes in DNA methylation, histone modifications and their modifying enzymes have been described in various tumor types, including colorectal cancer [4]–[6]. In this study, 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. "
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    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
    PLoS ONE 09/2014; 9(9-9):e108265-. DOI:10.1371/journal.pone.0108265 · 3.23 Impact Factor
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