Epigenetic dysregulation is common to many human diseases, especially cancer. DNA methylation, histone modifications, nucleosome remodeling, and RNA-mediated targeting are all epigenetic processes key to regulating the gene expression and proper functioning of biological processes. All of these processes can be perturbed in cancers and the various stages of tumor advancement, including tumorigenesis, promotion, progression, and recurrence, are all associated with specific epigenetic alterations, and many of these are targetable using epigenetic drugs which are emerging as an important class of anti-cancer pharmaceuticals¹.

In eukaryotic cells, genomic DNA is packaged around histones to form nucleosomes, which further compact to create higher-order chromatin structures. Nucleosomes are the fundamental structural units of chromatin. The spatial organization of chromatin plays a critical role in several processes, including nucleosome localization, the recruitment of transcriptional regulators, chromatin accessibility, and the regulation of gene expression. When compact, the structure of chromatin widely inhibits mRNA transcription, while accessible chromatin allows physical access to DNA facilitating interactions with transcriptional regulators, RNA polymerases and other DNA interacting proteins.

Epigenetic processes predominantly regulate alterations to the chromatin structure. Nucleosome remodeling is implicated in higher order folding of chromatin fibers reacts to shifts in epigenetic changes, including DNA methylation, histone modification, and RNA-mediated processes. Modifications of histone tails, mainly within chromatin fibers, serve as markers for gene expression and repression through the acetylation and methylation of various amino acids. Chromatin can store and transmit epigenetic information via DNA methylation and post-translational histone alterations. These changes are inherited during cell replication, making epigenetic dysregulation a common feature of almost all human cancers. Specifically, regulatory factors, in conjunction with an irregular genome structure or abnormal gene expression, can transform normal cells and tissues into malignant forms².

Protein complexes that affect epigenetic modifications can be classified into writers, readers, and erasers. Epigenetic writers are responsible for adding specific chemical modifications to DNA or histones, thereby creating epigenetic markers. Readers refer to methyl-CpG-binding domain proteins (MBPs), which recognize and translate these modified protein domains. Meanwhile, erasers are chromatin-modifying enzymes that remove the epigenetic markers.

DNA methylation occurs when DNA methyltransferases (DNMTs) add a methyl group to the C5 position of cytosine residues. This epigenetic modification is crucial in differentiating normal cells from cancerous and diseased cells, ensuring the precise regulation of gene expression. In the context of cancer, hypermethylation, and hypomethylation are relatively independent processes that contribute to the cancer genome and tumor progression³.

Furthermore, histone methylation is an imperative factor in determining the complex state of chromatin and is primarily regulated by lysine methyltransferases (KMTs) and lysine demethylases (KDMs). KMTs and KDMs function as writers and erasers in epigenetic regulation. In addition, various post-translational modifications of histones, including acetylation, methylation, phosphorylation, and ubiquitylation, play vital roles in regulating gene transcription epigenetically. Histone acetylation and deacetylation are the most typical post-translational modifications at the NH₂ terminal tail of core histones⁴.

Another major field of epitranscriptomics is RNA modification. Dynamic RNA modifications are marked by a new level of control over genetic information. Selective transcription factors can deposit specific alterations onto a set of transcripts, enabling the coordinated use and turnover of the transcriptome. This process is fundamental for regulating the cellular transcriptome during development. For example, N⁶-methyladenosine (m⁶A) is the most prevalent internal RNA methylation modification. It accelerates pre-mRNA processing and transport, affecting mRNA stability, splicing, and translation in mammalian cells⁵.

Cancer is a multifaceted disease influenced by genetic variations, epigenetic changes, and environmental factors. The epigenetic modifications that the three-dimensional organization of the genome governs are dynamic and can be reversed. Consequently, reversing epimutations is an essential focus for small-molecule inhibitors. Anticancer therapies targeting specific epigenetic mechanisms have shown promise in clinical trials, either as standalone treatments or in combination with other medicines⁶.

Our Cancer epigenetics poster illustrates a detailed and interactive overview of the key epigenetic regulatory mechanisms involved in cancer biology, especially DNA methylation, histone acetylation, and miRNAs.

References

1.    Dawson, M. A. & Kouzarides, T. Cancer epigenetics: from mechanism to therapy.  Cell   150, 12–27 (2012).

2.    Yu, X., Zhao, H., Wang, R. et al. Cancer epigenetics: from laboratory studies and clinical trials to precision medicine.  Cell Death Discov.   10, 28 (2024).

3.    Moore, L. D., Le, T. & Fan, G. DNA methylation and its essential function.  Neuropsychopharmacol.   38, 23–38 (2013).

4.    Hyun, K., Jeon, J., Park, K. & Kim, J. Writing, erasing and reading histone lysine methylations.  Exp. Mol. Med.   49, e324 (2017).

5.    Barbieri, I. & Kouzarides, T. Role of RNA modifications in cancer.  Nat. Rev. Cancer   20, 303–322 (2020).

6.    Cheng, Y. et al. Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials.  Sig. Transduct. Target Ther.   4, 62 (2019).