Methylation of Lysine 9 of Histone H3: Role of Heterochromatin Modulation and Tumorigenesis

This chapter focuses on the methylation of lysine 9 of histone H3 and the role of heterochromatin in cancer development. The histone H3 and H4 hold highly dynamic N-terminal ends rich in basic amino acids that are subjected to epigenetic modifications including reversible methylation, acetylation, ubiquitination, and phosphorylation. These modifications may act individually, sequentially, or in combination to form a "histone code" that regulates the assembly of nucleosome beads into higher order chromatin structures through interaction with other regulatory proteins. The initiation, propagation, and maintenance of heterochromatin is largely controlled by the formation of trimethylation of the lysine 9 on histone H3 (H3K9me3), along with some other synergistic epigenetic modifications. Considering the importance in controlling the packing and usage of genetic information, it has been recently recognized that alteration in chromatin structure due to epigenetic changes may be an event essential for cancer development. Post-translational modifications of the key lysine residues on histone proteins, most importantly histone H3, determine the formation of different chromatin structures. Among the well-documented histone modifications, it is fair to say that methylation of the N-terminal lysine residues of histone H3 is the most critical in this regard. Histone H3 certainly makes a causative contribution to both early and subsequent stages of cancer development. An intriguing question to be asked is whether changes in histone H3 can serve as a biomarker for the diagnosis and prognosis of cancers. Many challenges still remain in understanding its function and regulation in the malignant transformation of cells, carcinogenesis of the tissue, and tumorigenesis. Furthermore, there is an urgent need to assess the potential of targeting histone H3 or its regulatory signaling in cancer therapy.