Epigenetic regulation in cancer therapy: From mechanisms to clinical advances

This review is designed by Dr. Yinglan Zhao and written by her PhD students Dr. Lei Tao and Yue Zhou (Cancer Center and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University).

Epigenetic regulation is a dynamic and reversible process characterized by the addition and removal of modifications to DNA and histones. These modifications are carried out by chromatin-modifying enzymes in a tightly regulated and cooperative manner, resulting in changes to the structure of chromatin. The regulators responsible for these epigenetic modifications on DNA and histones have been classified into four main categories: "writers", "erasers", "readers", or "movers". Writers, as the name implies, introduce epigenetic marks onto DNA or histones, including DNA methyltransferases (DNMTs), histone methyltransferases (HMTs), and histone acetyltransferases (HATs). Erasers, on the other hand, remove epigenetic marks through the action of histone lysine demethylases (KDMs) and histone deacetylases (HDACs). Readers recognize or are recruited to specific epigenetic marks, such as chromodomain and bromodomain proteins recognizing methylated or acetylated residues, respectively. Movers are chromatin-remodeling proteins that change the dynamic spatio-temporal positioning of nucleosomes to allow for gene transcription. Epigenetic aberrations are commonly observed in cancer and are considered as hallmarks of cancer. In recent years, small molecules targeting specific epigenetic regulators have been developed and are demonstrating promising therapeutic potential in preclinical and clinical trials for cancer treatment.

Tao and Zhou comprehensively summarized the latest progress in comprehending the mechanisms of various epigenetic pathways, with a particular focus on DNA methylation, histone methylation, and histone acetylation, and discussed the dysregulation of the writers, readers, and erasers of epigenetic marks in hematologic malignancies and solid tumors. Besides, they summarized the current advances and challenges of cancer epigenetic therapy targeting these mechanisms. Finally, they discussed the potential benefits of combination therapies with epigenetic drugs and other therapeutic approaches. This review aims to shed light on the importance of epigenetics in both cancer development and treatment, hoping to help the potential applications of epigenetic drugs for cancer therapy in the future.