Cancer epigenetics: from laboratory studies and clinical trials to precision medicine

Abstract

Epigenetic dysregulation is a common feature of a myriad of human diseases, particularly cancer. Defining the epigenetic defects associated with malignant tumors has become a focus of cancer research resulting in the gradual elucidation of cancer cell epigenetic regulation. In fact, most stages of tumor progression, including tumorigenesis, promotion, progression, and recurrence are accompanied by epigenetic alterations, some of which can be reversed by epigenetic drugs. The main objective of epigenetic therapy in the era of personalized precision medicine is to detect cancer biomarkers to improve risk assessment, diagnosis, and targeted treatment interventions. Rapid technological advancements streamlining the characterization of molecular epigenetic changes associated with cancers have propelled epigenetic drug research and development. This review summarizes the main mechanisms of epigenetic dysregulation and discusses past and present examples of epigenetic inhibitors in cancer diagnosis and treatment, with an emphasis on the development of epigenetic enzyme inhibitors or drugs. In the final part, the prospect of precise diagnosis and treatment is considered based on a better understanding of epigenetic abnormalities in cancer.

Fig. 1. Epigenetic alterations associated with carcinogenesis.

Epigenetic alterations involve DNA methylation, histone acetylation, and miRNA regulation that have reversible effects on gene silencing and activation through epigenetic enzymes and related proteins. Writers (DNMT, HAT, and KMT) are enzymes that add acetyl (Ac) and methyl (Me) tags to histones. MBDs are readers that recognize methyl-CpG and modify histones. Erasers (DNA demethylase, HDAC, and KDM) are responsible for removing chemical groups from DNA or histones. Noncoding RNAs (miRNAs and lncRNAs) are also involved in epigenetic regulation. A DNA methylation in normal and cancer cells. The overall hypomethylation and local hypermethylation of promoter regions are characteristics of cancer cells. P: promoter region. B Methylation and demethylation of lysine or arginine in histones. Lysine can be methylated once (me1), twice (me2) or three times (me3) catalyzed by KMT. Arginine is methylated once (me1) or twice (me2) catalyzed by KMT. These processes can be reversed by KDM. C HDAC removes acetyl groups from histone lysine residues. Acetylated histones are considered “active chromatin” allowing gene transcription, whereas deacetylated histones are “non-active chromatin” associated with gene silencing. D The methylation of m⁶A is installed by the RNA methyltransferase complex with the catalytic subunit METTL3/METTL4 (writer) and removed by demethylases, such as FTO and ALKBH5 (eraser). m⁶A reader proteins (YTHDCs) can specifically bind m⁶A transcripts. DNMT, DNA methyltransferase; HAT, histone acetyltransferase; HDAC, histone deacetylase; KDM, lysine demethylase; KMT, lysine methyltransferase; m⁶A, N⁶-Methyladenosine. MBP, methyl-CpG-binding domain protein.

Fig. 2. Approaches contributing to personalized medicine.

A Multi-omics comprehensively analyzes the genome, transcriptome, and epigenetic panels of tumors from multiple perspectives. B Classification diagram of AI application in precision medicine.