Epigenetic Modifications in Cancer Biology

Epigenetic modifications encompass heritable changes in gene expression that do not involve alterations to the underlying DNA sequence. In cancer biology, these changes include DNA methylation, post-translational histone modifications (such as methylation, acetylation, ubiquitylation and phosphorylation) and the action of non-coding RNAs. Collectively, they regulate chromatin accessibility and influence critical processes such as transcriptional initiation, elongation, DNA repair and cell-cycle progression. Dysregulation of epigenetic writers (enzymes that deposit marks), erasers (enzymes that remove marks) and readers (proteins that interpret marks) can lead to aberrant silencing of tumour suppressor genes or activation of oncogenes. For instance, hypermethylation of promoter CpG islands frequently silences key regulatory genes, while loss of repressive histone marks can facilitate malignant transformation. The dynamic and reversible nature of these mechanisms underpins tumour plasticity, metastasis and the emergence of drug resistance. Understanding the interplay between different layers of chromatin regulation has profound implications for biomarker development and the design of epigenetic therapies that aim to restore normal patterns of gene expression.

Research from Nature Portfolio

Recent studies have elucidated distinct roles for specific histone marks in shaping transcriptional dynamics. Work on trimethylation of histone H3 lysine 4 (H3K4me3) has revealed that, rather than initiating transcription, this mark is crucial for release of paused RNA polymerase II and efficient elongation. Loss of H3K4me3 leads to widespread reduction in transcriptional output and highlights the dependency of cancer cells on precise pause-release mechanisms for the expression of growth-promoting genes. In parallel, early clinical trials have demonstrated that selective inhibition of histone acetyltransferases KAT6A and KAT6B yields antitumour activity in heavily pretreated oestrogen receptor-positive metastatic breast cancer. A first-in-human phase 1 study showed a tolerable safety profile, objective responses and prolonged progression-free survival when the inhibitor was given alone or with endocrine therapy. These findings validate KAT6A/B as druggable targets and establish a framework for epigenetic combination strategies in solid tumours.

Epigenetic Modifications in Cancer Biology publication trend

The graph below shows the total number of articles in epigenetic modifications in cancer biology across all publications each year (not limited to Nature Index journals).

Technical terms

DNA methylation: Addition of a methyl group to cytosine residues, often leading to gene silencing.

Histone acetyltransferase (HAT): Enzyme that adds acetyl groups to histone lysines, generally associated with active transcription.

Histone demethylase: Enzyme that removes methyl groups from histones, modulating chromatin structure and gene expression.

RNA polymerase II pausing: A regulatory step in which polymerase transiently halts near the promoter before productive elongation.

Writers, erasers, readers: Classes of proteins that deposit, remove or interpret epigenetic marks on chromatin.

References

1. H3K4me3 regulates RNA polymerase II promoter-proximal pause-release. Nature (2023).
2. Inhibition of lysine acetyltransferase KAT6 in ER+HER2− metastatic breast cancer: a phase 1 trial. Nature Medicine (2024).
3. Targeting epigenetic regulators to overcome drug resistance in cancers. Signal Transduction and Targeted Therapy (2023).
4. Recycling of modified H2A-H2B provides short-term memory of chromatin states. Cell (2023).