Epigenetic modifications are changes to the genome that do not involve a change in the nucleotide sequence.1 They are essential for normal development and maintenance of tissue-specific gene expression patterns in mammals.2,3


Epigenetic mechanisms involved in regulating gene expression and chromatin structure in normal mammalian cells include2-4:

  • DNA methylation
  • Covalent histone modifications
  • Nucleosome positioning and histone variants
  • microRNAs (miRNAs)4

Histone post-translational modifications (PTMs) are key regulators of gene expression.4

  • Histone writers, erasers, and readers are protein machinery that add, remove, or recognize PTMs.
  • This protein machinery plays an important role in transcriptional responses.

Oncogenic Expression

Global changes in the epigenetic landscape are a hallmark of cancer.2,3

Disruption of epigenetic processes can lead to altered gene function and malignant cellular transformation.2,3 Abnormal epigenetic modifications can contribute to tumorigenesis and resistance to cancer therapy by1,3-6:

  • Activating oncogenes
  • Deactivating tumor suppressor genes and genes involved in the immune response
  • Suppressing terminal differentiation
  • Affecting tumor heterogeneity

Therapeutic Potential

Pharmacological research in this area focuses on approaches to cancer treatment that include inhibiting the epigenetic mechanisms involved in histone modifications, chromatin remodeling, and transcription regulation.6

Strategies for addressing epigenetic modifications therapeutically include targeting writers, erasers, and readers as well as other pathways that regulate gene expression, such as PARP and BET.2,3

  • PARP inhibition may lead to accumulation of single- and double-strand DNA breaks in tumor cells that may have limited capacity for repair or are exposed to DNA-damaging agents, resulting in apoptosis.
  • BET family (BRD2, BRD3, BRD4, and BRDT) protein inhibition can impair tumor cell DNA transcription and induce apoptosis.
  1. Valdespino V, Valdespino PM. Potential of epigenetic therapies in the management of solid tumors. Cancer Manag Res. 2015;7:241-251.
  2. Pfister SX, Ashworth A. Marked for death: targeting epigenetic changes in cancer. Nat Rev Drug Discov. 2017;16(4):241-263.
  3. Caiafa P, Guastafierro T, Zampieri M. Epigenetics: poly(ADP-ribosyl)ation of PARP-1 regulates genomic methylation patterns. FASEB J. 2009;23(3):672-678.
  4. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646-674.
  5. Falahi F, Sgro A, Blancafort P. Epigenome engineering in cancer: fairytale or a realistic path to the clinic? Front Oncol. 2015;5:22. doi: 10.3389/fonc.2015.00022. Epub 6 Feb 2015.
  6. Easwaran H, Tsai H-C, Baylin SB. Cancer epigenetics: tumor heterogeneity, plasticity of stem-like states, and drug resistance. Mol Cell. 2014;54(5):716-727.

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