Histone modification is an epigenetic mechanism by which more than 100 different post-translational modifications may occur at the amino-terminal ends of the histone tails in nucleosomes. Such modifications contain methylation, acetylation, ubiquitination, phosphorylation, among others. You can click here to know more information about four common histone modifications.
These modifications can cause the activation or repression of gene transcription, depending on the identity and location of the amino acid residue that is modified. Histones are key players in epigenetics and many diseases develop when abnormities emerge in the epigenetic mechanisms. Once we mention epigenetics, two factors will come to our mind, DNA methylation and histone modification. In this section, we mainly focus on the relationship between histone modification and cancer.
Cancer is a group of diseases involving abnormal cell growth with the potential to invade or spread to other parts of the body. Emerging evidence has suggested that epigenetic dysregulation is being increasingly recognized as a hallmark of cancer [1]. Moreover, many studies have explored the mosaic patterns of histone modification in cancer cells on a gene-by-gene basis, and these results have revealed the crucial role of CpG-island-promoter hypermethylation in transcriptional silencing of tumour-suppressor genes and is a normal event in the regulation of cellular gene expression [2]. Additionally, a large number of studies have uncovered that promoter CpG-island hypermethylation in cancer cells is known to be associated with a particular combination of histone marks, involving loss of histone H3 lysine K4 (H3K4) trimethylation, deacetylation of histones H3 and H4, and gain of H3K9 methylation and H3K27 trimethylation[3] [4] [5].
For instance, in 2007, the team of Meng CF has demonstrated that hypermethylation of DNA in promoter CpG islands is related to transcriptional silencing of tumor suppressor genes by ChIP assays. Histone H3-K9 methylation in different regions of the promoters studied correlates with DNA methylation status of each gene in gastric cancer cells [6]. In his study, when the CpG islands were hypermethylated, trichostatin A (TSA, one kind of histone deacetylase inhibitors) increased histone acetylation, but had almost no effect on gene expression. In contrast, 5-Aza-dC (one kind of DNA methylation inhibitors) reactivated expression of hypermethylation- induced silenced genes. This result may suggest that alteration of DNA methylation affects histone modification.
Additionally, histone modification also is a good biomarkers of cancer prognosis. In gastric cancers, as an example, Immunohistochemistry analysis of gastric adenocarcinomas showed that global levels of trimethylation of H3K9 (H3K9me3) were positively associated with tumor stage, lymphovascular invasion, and cancer recurrence. Moreover, higher level H3K9me3 correlated with a poor survival rate [7]. While a genome wide analysis of H3K27me3, which is a mark of transcriptional repression, via ChIP-Chip demonstrated that 128 genes displayed significant differences in H3K27me3 levels, with 119 genes exhibiting increased levels of the mark and nine a decrease level [8].
References
[1] Yana Chervona and Max Costa. Histone modifications and cancer: biomarkers of prognosis [J]? Am J Cancer Res. 2012; 2(5): 589–597.
[2] Esteller M. Cancer epigenomics: DNA methylomes and histone-modification maps [J]. Nat Rev Genet.2007 8(4):286-98.
[3] Fahrner, J. A., Eguchi, S., et al. B. Dependence of histone modifications and gene expression on DNA hypermethylation in cancer [J]. Cancer Res. 2002, 62, 7213–7218.
[4] Ballestar, E. et al. Methyl-CpG binding proteins identify novel sites of epigenetic inactivation in human cancer [J]. EMBO J. 2003, 22, 6335–6345.
[5] Vire, E. et al. The Polycomb group protein EZH2 directly controls DNA methylation [J]. Nature. 2006, 439, 871–874.
[6] Meng CF, Zhu XJ, et al. Re-expression of methylation-induced tumor suppressor gene silencing is associated with the state of histone modification in gastric cancer cell lines [J]. World J Gastroenterol. 2007, 13(46):6166-71.
[7] Park YS, Jin MY, et al. The global histone modification pattern correlates with cancer recurrence and overall survival in gastric adenocarcinoma [J]. Ann Surg Oncol. 2008; 15:1968–1976.
[8] Zhang L, Zhong K, et al. Genomewide analysis of histone H3 lysine 27 trimethylation by ChIP-chip in gastric cancer patients [J]. J Gastroenterol. 2009; 44:305–312.
CUSABIO team. Histone modification and Cancer. https://www.cusabio.com/c-20828.html
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