Epigenetic cancer therapy: Targets and strategies

Epigenetic events shape cancer initiation and progression. By targeting mechanisms involved in epigenetic regulation, epigenetic therapeutics serve as effective weapons against cancer.

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Epigenetic cancer therapy: Targets and strategies
Illustrated by Jerry Mensah

Inhibiting histone deacetylation

Histone deacetylases (HDACs) remove acetyl groups from histone lysine residues, leading to closed chromatin structures and gene silencing. HDAC mutations aberrantly deacetylate or inactivate tumor suppressor genes that slow cell division, promoting cancer development (1). HDAC inhibitor drugs upregulate tumor suppressor genes and inhibit cancer cell growth. 

Targeting DNA methylation

DNA methylation by DNA methyltransferases (DNMTs) blocks transcriptional factor binding and disrupts gene activity, triggering many cancer types. DNMT blockade drugs effectively prevent DNA hypermethylation and inhibit tumor progression (2).

Modifying histone methylation

Lysine-specific histone demethylase 1 (LSD1), enhancer of zeste homolog 2 (EZH2), and disruptor of telomeric silencing 1-like (DOT1L) selectively methylate or demethylate specific histone lysine residues, regulating histone-DNA interactions and assorted cellular processes. LSD1, EZH2, or DOT1L overexpression causes cancer, making their inhibitors promising potential therapeutics (1).

Changing RNA modification

As critical epigenetic modulators, noncoding RNAs undergo methylation modification mediated by methyltransferase-like protein 3 (METTL3), affecting RNA structures and functions. Changes to RNA methylation machinery influence tumor cell proliferation and differentiation (3). Reversing abnormal RNA methylation by targeting METTL3 represents a novel approach to cancer treatment. 


  1. Cheng, Y. et al. Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials. Sig Transduct Target Ther  4, 1–39 (2019). 
  2. Hu, C., Liu, X., Zeng, Y., Liu, J. & Wu, F. DNA methyltransferase inhibitors combination therapy for the treatment of solid tumor: mechanism and clinical application. Clinical Epigenetics  13, 166 (2021). 
  3. Yang, X. et al. Epigenetic modulations of noncoding RNA: a novel dimension of Cancer biology. Molecular Cancer  19, 64 (2020).

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