Histone Modifications and Cancer

Histone modifications represent an epigenetic mechanism through which over 100 distinct post-translational modifications can occur on the amino-terminal tails of histones within nucleosomes. These modifications encompass methylation, acetylation, ubiquitination, and phosphorylation, among others.

 

Histone modifications represent an epigenetic mechanism through which over 100 distinct post-translational modifications can occur on the amino-terminal tails of histones within nucleosomes. These modifications encompass methylation, acetylation, ubiquitination, and phosphorylation, among others. For a deeper understanding of the four common histone modifications, click here.

These modifications can lead to the activation or repression of gene transcription, depending on the nature and location of the modified amino acid residues. Histones play a pivotal role in epigenetics, and numerous diseases arise from abnormalities in epigenetic mechanisms, with DNA methylation and histone modifications being two prominent factors that come to mind. This section primarily delves into the relationship between histone modifications and cancer.

 

 

Cancer, a group of diseases characterized by abnormal cell growth, has the potential to invade or spread to other parts of the body. There is growing evidence that epigenetic dysregulation is considered one of the hallmarks of cancer [1]. Furthermore, numerous gene-based studies have explored the mosaic patterns of histone modifications in cancer cells, revealing that CpG-island-promoter hypermethylation plays a crucial role in the transcriptional silencing of tumor suppressor genes, which is a normal event in the regulation of cellular gene expression [2]. Additionally, extensive research has found that the promoter CpG-island hypermethylation in cancer cells is associated with specific combinations of histone marks, including the loss of histone H3 lysine K4 (H3K4) trimethylation, histone H3 and H4 deacetylation, H3K9 methylation, and H3K27 trimethylation gains [3] [4] [5].

For instance, in 2007, Meng CF's team demonstrated through ChIP assays that the hypermethylation of CpG island DNA in promoters is associated with the transcriptional silencing of tumor suppressor genes. Their study correlated the methylation status of histone H3-K9 at different regions of the promoters with the DNA methylation status of genes in gastric cancer cells [6]. In their research, when CpG island methylation levels were excessively high, trichostatin A (TSA, a histone deacetylase inhibitor) increased histone acetylation but had little impact on gene expression. In contrast, 5-Aza-dC (a DNA methylation inhibitor) was able to reactivate the expression of genes silenced by hypermethylation. This finding suggests that changes in DNA methylation can influence histone modifications.

 

 

Moreover, histone modifications serve as excellent biomarkers for cancer prognosis. In the case of gastric cancer, immunohistochemical analysis of gastric adenocarcinomas revealed that the overall level of H3K9 trimethylation (H3K9me3) positively correlates with tumor stage, lymphatic invasion, and cancer recurrence. Furthermore, higher levels of H3K9me3 are associated with lower survival rates [7]. A genome-wide analysis using ChIP-chip for the transcriptional repression mark H3K27me3 showed significant differences in H3K27me3 levels in 128 genes, with 119 genes exhibiting increased H3K27me3 levels and 9 genes displaying decreased levels [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