DNA methyltransferases and histone deacetylases (DNMTs/HDACs)

DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) are essential epigenetic enzymes that cooperatively regulate gene expression by modifying DNA and chromatin structure. DNMTs catalyze the addition of methyl groups to cytosine residues in DNA, typically leading to gene silencing, while HDACs remove acetyl groups from histone tails, promoting a condensed and transcriptionally inactive chromatin state (heterochromatin). In many diseases, particularly cancer, these enzymes are frequently overexpressed or dysregulated, resulting in the epigenetic silencing of tumor suppressor genes and the evasion of immune detection. Targeting both DNMTs and HDACs, either through combination therapy or dual-acting small molecules, has demonstrated significant therapeutic synergy. This dual inhibition not only reactivates silenced genes but also triggers a "viral mimicry" response by inducing the expression of endogenous retroviral elements, which activates the RIG-I/MDA5-MAVS signaling pathway and enhances anti-tumor immunity. Clinically, DNMT and HDAC inhibitors are used to treat various hematological malignancies and are being extensively investigated in solid tumors to sensitize them to immunotherapy and overcome drug resistance.

Other names

DNA methyltransferase and histone deacetylaseDNMT/HDAC dual targetEpigenetic modifiersDNMTi/HDACi combination

Inhibition of DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) leads to DNA demethylation and histone hyperacetylation, which reactivates silenced tumor suppressor genes and induces a viral mimicry response through the expression of endogenous retroviral elements (ERVs).