Interplay between Epigenetics and Genetics in Cancer

Abstract

Genomic instability, which occurs through both genetic mechanisms (underlying inheritable phenotypic variations caused by DNA sequence-dependent alterations, such as mutation, deletion, insertion, inversion, translocation, and chromosomal aneuploidy) and epigenomic aberrations (underlying inheritable phenotypic variations caused by DNA sequence-independent alterations caused by a change of chromatin structure, such as DNA methylation and histone modifications), is known to promote tumorigenesis and tumor progression. Mechanisms involve both genomic instability and epigenomic aberrations that lose or gain the function of genes that impinge on tumor suppression/prevention or oncogenesis. Growing evidence points to an epigenome-wide disruption that involves large-scale DNA hypomethylation but specific hypermethylation of tumor suppressor genes, large blocks of aberrant histone modifications, and abnormal miRNA expression profile. Emerging molecular details regarding the modulation of these epigenetic events in cancer are used to illustrate the alterations of epigenetic molecules, and their consequent malfunctions could contribute to cancer biology. More recently, intriguing evidence supporting that genetic and epigenetic mechanisms are not separate events in cancer has been emerging; they intertwine and take advantage of each other during tumorigenesis. In addition, we discuss the collusion between epigenetics and genetics mediated by heterochromatin protein 1, a major component of heterochromatin, in order to maintain genome integrity.

Keywords: epigenomics; genetics; heterochromatin-specific nonhistone chromosomal protein HP-1; neoplasms.

Fig. 1

On the road to cancer: genomic instability. Failure of DNA damage responses that conduct surveillance and checkpoints to guard genome causes genomic instability, the most common characteristic of human cancers. It has therefore been proposed that genomic instability contributes to and drives tumor initiation and development. Defects in the DNA damage responses generate genomic instability and facilitate tumorigenesis.

Fig. 2

Epigenetic mechanisms. Variations in chromatin structure but not DNA sequences modulate the use of the genome by 1) DNA methylation, 2) histone modifications (methylation, phosphorylation, and acetylation), 3) histone variant composition (dark), 4) chromatin remodeling (sparse or dense nucleosome occupancy), and noncoding RNAs.

Fig. 3

Epigenetic silencing is more frequent that mutations in cancer cells. In cancer cells, hundreds to thousands of genes are hypermethylated (DNA methylation), histone codes at more than thousands of genes are aberrantly modified via histone modifications or histone variant compositions, and miRNA expression is dysregulated, while tens of genes are affected by mutations. Both epigenetic silencing and inactivating mutations or deletions result in gene inactivation.

Fig. 4

(A) Heterochromatin protein 1 (HP1) paralogs in human. Amino acid sequence alignment of HP1α, β, and γ. (B) A schematic diagram of the HP1γ polypeptide. The HP1γ polypeptide has an N-terminal chromodomain, a hinge domain, and C-terminal chromoshadow domain.

Fig. 5

Interactions of heterochromatin protein 1 (HP1) with a diversity of proteins and its possible roles (references in parentheses). The putative cellular functions of protein-protein interactions of HP1 are shown in circles. Some of their biological significance is not yet clarified. Only the proteins that have been shown to interact with HP1 in vivo are listed here.