| Approximately 22,500 new cases of primary brain tumors occur annually in the United States, accounting for 1.4% of all tumors and 2.3% of cancer-related deaths. Glioma represents more than 70% of all brain tumors, including low-grade glioma (WHO grade 1 and 2) and high-grade glioma (WHO grade 3 and 4). Despite recent advances in surgery, radiotherapy, and chemotherapy, survival of glioma patients remains poor. The 5-year survival rates of low-grade glioma is 30-70% depending on histology, and the median survival is only 12 to 15 months for the most frequent and malignant glioblastoma. Previous studies have shown that several tissue-specific molecular events could modulate the tumorigenesis and progression of glioma, and that the malignancy of glioma is closely related to the expression, mutation or loss of several specific genes, which ultimately enable the tumor cells proliferate endlessly and uncontrolled, while the tumor itself grow and degenerate even worsely. Besides genetic alterations, many studies have shown that epigenetic modifications, including DNA methylation and histone modification, are critical to the development and progression of cancer by disrupt normal patterns of gene expression. Therefore evaluation of multiple histone modifications may help understanding the molecular mechanisms of the tumorigenesis and progression of gliomain, and may provide a rationale to modify chemotherapy with drugs such as histone deacetylase inhibitors.Epigenetics was defined as heritable changes in gene expression that are not a result of any alteration in the DNA sequence, whose mechanisms include but are not limited to aberrant DNA methylation, histone modification and microRNAs. The best-known epigenetic marker is DNA methylation. Hypermethylation of the CpG-island promoter can induce silencing of genes (first reported by Feinberg et al.) affecting the cell cycle, DNA repair, metabolism of carcinogens, cell-to-cell interaction, apoptosis, and angiogenesis, all of which may occur at different stages in cancer development and interact with genetic lesions. In addition to DNA promoter hypermethylation, one emerging model called"histone code"hypothesis (raised by Stahl et al.) assumes that specific combinations of histone modifications may confer the overall expression status of a region of chromatin, which may also contribute to carcinogenesis. In contrary to the changes in DNA sequencies, epigenetic changes are reversible, which means the alteration of an abnormal epigenetic pattern may serve as a treatment for cancer patients (the so-called"epigenetic therapy"). Currently, histone modifications were studied in both specifically and globally levels, and were shown to affect several steps of tumor cell biology and have a prognostic value in several cancer patients such as prostate cancer, gastric cancer, esophagus cancer, breast cancer, and cervical cancer. However, few was known about the histone modification patterns in glioma. Thus, we performed this study to evaluate the modification patterns of several histones in patients with glioma and to investigate its role in the tumorigenesis and progression of glioma.Purpose To investigate the relationship between epigenetic changes involving multiple modifications of histones and pathological grades in astrocytomas. Methods Immunohistochemistry was performed to evaluate the level of histone 3 lysine 4 dimethylation (H3K4diMe), histone 4 lysine 12 (H4K12Ac) and histone 3 lysine 18 (H3K18Ac) in resected tumor samples of 67 astrocytoma patients and in normal brain tissue of 10 non-cancer patients. Results H3K4diMe, H4K12Ac and H3K18Ac were all detected at high frequencies in tumor tissue of astrocytoma, while none of the control normal brain tissue showed abovementioned histone modification. The expression of H3K4diMe and H4K12Ac were positively correlated with increasing WHO grades (P<0.05), while H3K18Ac staining was not significantly correlated with WHO grades. Conclusion Multiple modifications of histones may affect several steps in tumor cell biology, and may have a prognostic value in astrocytomas since specific modifications were correlated with WHO grades. |
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