Targeting the cancer epigenome for therapy

Key Points

  • Tumour cells often have mutations in genes that encode regulators of the epigenome.

  • Cancers use both genetic and epigenetic alterations to evolve and develop resistance to immune surveillance and chemotherapy.

  • DNA methylation inhibitors are the standard of care for certain haematological malignancies and form the backbones of many trials in solid tumours.

  • Several new drugs that target histone modifications are being tested in clinical trials.

  • DNA methylation inhibitors activate not only abnormally silenced genes, but also cancer testis antigens (CTAs) and endogenous retroviruses (ERVs). Activation of CTAs and ERVs may increase the visibility of the tumour to the immune system and increase the efficacy of immunotherapy.

  • Therapies that combine epigenetic drugs and standard chemotherapy will become important clinical tools in the future.


Next-generation sequencing has revealed that more than 50% of human cancers harbour mutations in enzymes that are involved in chromatin organization. Tumour cells not only are activated by genetic and epigenetic alterations, but also routinely use epigenetic processes to ensure their escape from chemotherapy and host immune surveillance. Hence, a growing emphasis of recent drug discovery efforts has been on targeting the epigenome, including DNA methylation and histone modifications, with several new drugs being tested and some already approved by the US Food and Drug Administration (FDA). The future will see the increasing success of combining epigenetic drugs with other therapies. As epigenetic drugs target the epigenome as a whole, these true 'genomic medicines' lessen the need for precision approaches to individualized therapies.

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Figure 1: Modulation of covalent modifications on chromatin.
Figure 2: Somatic inheritance of acquired traits in cancer.
Figure 3: Targeting chromatin for therapy.
Figure 4: Activation of constitutively and de novo methylated elements by DNMT inhibitors.


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Research funding was provided by the Van Andel Research Institute–Stand Up To Cancer (SU2C) Epigenetics Dream Team, of which the authors are members. SU2C is a programme of the Entertainment Industry Foundation (EIF), administered by the American Association for Cancer Research (AACR). P.A.J. is supported by the US National Cancer Institute (RO1 CA082422). J.-P.J.I. is supported by the US National Institutes of Health (NIH) (CA158112 and CA100632) and by a grant from the Ellison Medical Foundation. He is also an American Cancer Society Clinical Research Professor supported by a generous gift from the F.M. Kirby Foundation. S.B. receives support from the NIH (R01 CA170550), the EIF Jim Toth Sr. Breakthrough Lung Cancer Research Award, the Rising Tide Foundation and SU2C (SU2C-AACR-CT0109).

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Correspondence to Peter A. Jones.

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Competing interests

P.A.J. is a paid consultant for Zymo Corporation. S.B. has consulted for Celgene Corporation, Astex Pharmaceuticals, Chugai Pharmaceuticals, Merck–Pfizer and Merck & Co. regarding some of the work mentioned. J.-P.J.I. is a consultant for and has received research support from Astex Pharmaceuticals.

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Enzymes that apply covalent modifications, such as methyl or acetyl groups, to specific amino acids on histones.


Proteins that can recognize specific modifications on histones at defined positions in the protein backbone.


The reversibility of epigenetic marks on DNA and proteins.


Enzymes that can remove specific modifications at defined sites on DNA or histones.

TET family

The ten-eleven translocation family of α-ketoglutarate-dependent dioxygenases catalyse the oxidation of 5-methlcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further products. Genes encoding these enzymes are frequently mutated in human cancers.


A gene in which the activation or deactivation of expression is causally related to the establishment of the malignant state.

Genomic medicines

Drugs that have wide-ranging effects on the epigenome.

Precision medicine

The use of drugs to target specific abnormalities identified in a patient.

Synthetic lethality

A relationship between two genes in which the combined inactivation of the genes results in cell death, whereas the inactivation of either gene alone has no effect. It can also refer to a gene whose perturbation only results in cell death in the presence of a particular cellular feature (for example, a mutation).


(Long interspersed nuclear elements). Highly repetitious elements that make up a considerable portion of the human genome; their methylation status can be used as a surrogate for overall genomic methylation.

Alu elements

Interspersed DNA sequences of about 300bp that belong to the short interspersed element (SINE) family and are found in the genome of primates.

Frontline therapy

The use of a drug early in treatment before other drugs have been used.

CCCTC-binding factor sites

(CTCF sites). Binding sites for the CTCF transcription factor, which is involved in transcriptional activation, insulator activity and regulation of chromatin architecture.

Cancer testis antigens

(CTAs). A group of proteins expressed during male germ cell development, which are silenced in normal cells and may become re-expressed ectopically in cancers. Many are highly immunogenic.


The use of a single drug to treat a malignancy.

Immune checkpoint therapy

The use of antibodies that target regulatory pathways in T cells to enhance antitumour immune response.

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Jones, P., Issa, J. & Baylin, S. Targeting the cancer epigenome for therapy. Nat Rev Genet 17, 630–641 (2016).

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