Cancer Related Erosion of the Epigenetic Landscape

Epigenetics and Aging (16)

The net result of cell differentiation during embryonic development is 200 distinct epigenetic landscapes. The differences between cell types, their identity, comes down to which genes are epigenetically deactivated, permanently. This deactivation requires constant epigenetic maintenance over the course of countless cell divisions. Cancer associated changes in the cell can be viewed as the erosion of its epigenetic landscape.

Every type of cancer has its own biological signatures, genetic and epigenetic, by means of which it can be precisely classified through the various stages of its development. Some cancers, though, share a subset of their biological signatures. Here I will consider some epigenetic changes shared by many, but certainly not all cancers. In this post I will discuss dysregulation of DNA methylation and histones; in the next I will consider dysregulation of noncoding RNAs.

DNA Methylation Dysregulation

Let’s first consider what happens when DNA methylation goes off the rails during cancer development. Briefly, by way of recap, methylation generally has an inhibitory effect on gene activity (called expression, the term I will use henceforth). DNA methylation is an important dimension of a cell’s epigenetic landscape, and hence identity. Much of cell differentiation depends on where in the cellular genome DNA methylation occurs, which genes are permanently deactivated, and which are not.

Cancer is associated with the demethylation of normally methylated regions and the methylation of formerly non-methylated regions. One of the early signatures of cancerous cells is the loss of methylation or hypomethylation. The result is a host of proteins and RNAs that shouldn’t be present in that cell type, and hence cellular metabolic dysregulation. Moreover, the loss of methylation releases the hounds of transposable elements, which are now free to move around the genome and insert themselves willy nilly. Genomic integrity is compromised thereby, increasing the probability of somatic mutations (https://doi.org/10.1016/j.tig.2021.05.002).

Equally important is the methylation of normally unmethylated genomic regions of the cell. This includes so-called housekeeping genes, which are never deactivated in any cell type

 because they are essential for basic cell functions common to all. Among the cancer-related genes that become hypermethylated are those called tumor suppressors.

The name, tumor suppressor, is a misleading residue of the somatic mutation theory of cancer, implying, as it does, that this gene only functions in a cancerous environment. Quite the contrary, this family of genes has very basic functions, in controlling the rate of cell division in normal cells, as well as the rate of apoptosis, the death of aging cells.

Histone Dysregulation

Histone dysregulation is another hallmark of cancer. Histones are the proteins with which DNA is inextricably bound in chromatin, the stuff of which chromosomes are made. There are five canonical histones, which can be independently modified in several ways. The best studied histone modification are methylation, acetylation and phosphorylation, but there are others, and the list is growing. Here I will only consider methylation and acetylation. As noted in previous posts, these modifications occur on particular amino acids at particular places on the histone protein.

Histones 3 and 4 (H3 and H4) are important in establishing cell identity. I will focus on H3. Methylated histones generally repress gene expression in adjacent DNA. Methylation of H3 comes in three degrees, mono-methylation, bi-methylation and tri-methylation, corresponding to strength of inhibition. But the influence of methylated H3 on cell identity is a function of the specific gene promoters to which it binds, which varies from cell type to cell type (35562425).

The activating effects of H3 by way of acetylation are similarly cell type specific, with respect to the affected genes.

Cancer is associated with the breakdown in this cell type specificity in the activating and deactivating effects of H3 and other canonical histones. Genes normally deactivated by H3 can become activated and genes normally activated by H3 can become deactivated. Moreover, several canonical histones have well known variants that differ slightly in their amino acid sequence. Some variants of H2 and H3 are important in establishing and maintaining cell identity. Other variants though, are known to be upregulated in specific cancers.

Most of the epigenetic anti-cancer drugs developed to date are designed to reverse cancer-related histone modifications, and altered levels of canonical histone variants (https://doi.org/10.1016/j.semcancer.2020.07.015).