Review
Epigenetic mechanisms of importance for drug treatment

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Highlights

There are pronounced interindividual variations in drug metabolism, drug responses, and the incidence of adverse drug reactions. To a certain extent such variability can be explained by genetic factors, but epigenetic modifications, which are relatively scarcely described so far, also contribute. It is known that a novel class of drugs termed epidrugs intervene in the epigenetic control of gene expression, and many of these are now in clinical trials for disease treatment. In addition, disease prognosis and drug treatment success can be monitored using epigenetic biomarkers. Here we review these novel aspects in pharmacology and address intriguing future opportunities for gene-specific epigenetic editing.

Section snippets

Pharmacoepigenetics

During the last decade much information has accumulated regarding the genetic causes of differences in drug responses. This has led to the identification of many pharmacogenomic biomarkers important for individualized drug therapy, particularly in cancer treatment, that are currently in clinical use. Such biomarkers help to avoid severe complications of drug treatment, which are estimated to cost billions of dollars and cause 100,000 deaths in the USA annually. However, only 20–30% of the

Basics of epigenetics

The current definition of epigenetics is changes in gene function that can be inherited via cellular divisions and cannot be explained by any change in the primary sequence of nucleic acids. In contrast to germline genetic variants, which are inherited from progenitors and are stable across lifespan, epigenetic signatures can be generated in response to various external or internal stimuli. Moreover, epigenetic regulation constitutes a means whereby an organism can ‘remember’ the altered gene

Epigenetic regulation of ADME genes

Epigenetic modifications and other factors within the complex regulatory network are able to influence ADME gene expression in cis and in trans 30, 31, 32. In addition, the epigenetic regulation of gene expression can be modulated by environmental factors such as drugs, diet, and environmental pollutants [33]. Therefore, knowledge of the intrinsic and extrinsic factors that influence epigenetic signatures in ADME genes is of importance for understanding interindividual variations in drug

Epidrugs

Epidrugs can be defined as drugs that inhibit or activate disease-associated epigenetic proteins for ameliorating, curing, or preventing the disease. In many human diseases, particularly cancer, the expression or activity of epigenetic proteins is altered. Epigenetic alterations are observed very early during cell transformation, and thus are driver rather than passenger events in cancer 40, 41. The use of epidrugs may thus represent a step forward in the therapy of cancer and other diseases in

Epidrugs for treatment of drug abuse

The addiction phenotype represents a long-term molecular memory of drug consumption, suggesting the existence of strong epigenetic components. Drugs of abuse might thus influence the activity of certain epigenetic proteins, and epidrugs might possibly be developed as a novel pharmacological intervention for drug addiction. Indeed, morphine-treated mice demonstrated decreased HDAC activity and increased histone H3 acetylation in the spinal cord, and administration of the histone

Epigenetic editing

As mentioned, a common feature of epigenetic proteins is that they lack an intrinsic sequence recognition capability, and modulation of their activity by epidrugs can theoretically cause genome-wide gene expression changes. Hence, the general disadvantage of epidrugs is their potential lack of specificity, which can result in serious side effects. An alternative to epidrugs that may counteract this limitation is the novel approach of epigenetic editing, which can be defined as intentional

Concluding remarks

The field of pharmacoepigenetics is rapidly growing and our understanding of the roles of epigenetic mechanisms in drug action is increasing, as summarized in Figure 7. It is apparent that epigenetic modifications induced by drugs and other xenobiotics can act as short- and long-term regulatory mechanisms for drug dependence, drug resistance, and altered drug metabolism and action. There is a need to investigate to what extent xenobiotic exposure can influence epigenetic signatures in the human

Acknowledgments

Research at our laboratory is funded by grants from The Swedish Research Council, The Swedish Cancer Fund, FP-7/Seurat 1 project NOTOX, IMI-JU project MIP-DILI, and Marie Curie grant CIG 322283.

Glossary

Bromodomains
protein domains responsible for recognition of acetylated lysine residues in histones, thus mediating the effect of histone acetylation on gene transcription.
DNA hydroxymethylation
modification of 5-methylcytosine by oxidation of the methyl group (-CH3) to a hydroxymethyl group (-CH2-OH), yielding 5-hydroxymethylcytosine (5hmC).
DNA methylation (DNAme)
modification of cytosine residues in DNA by addition of a methyl group (-CH3) to the fifth position of a cytosine base, yielding

References (93)

  • M. Kacevska

    DNA methylation dynamics in the hepatic CYP3A4 gene promoter

    Biochimie

    (2012)
  • S. Kalari et al.

    Identification of driver and passenger DNA methylation in cancer by epigenomic analysis

    Adv. Genet.

    (2010)
  • J.M. Foulks

    Epigenetic drug discovery: targeting DNA methyltransferases

    J. Biomol. Screen.

    (2012)
  • R. Hewitson

    Heart failure: the pivotal role of histone deacetylases

    Int. J. Biochem. Cell Biol.

    (2013)
  • J.C. Black

    Histone lysine methylation dynamics: establishment, regulation, and biological impact

    Mol. Cell

    (2012)
  • P. Anand

    BET bromodomains mediate transcriptional pause release in heart failure

    Cell

    (2013)
  • M.M. Matzuk

    Small-molecule inhibition of BRDT for male contraception

    Cell

    (2012)
  • P. Filippakopoulos

    Benzodiazepines and benzotriazepines as protein interaction inhibitors targeting bromodomains of the BET family

    Bioorg. Med. Chem.

    (2012)
  • D.Y. Liang

    Epigenetic regulation of opioid-induced hyperalgesia, dependence, and tolerance in mice

    J. Pain

    (2013)
  • E.J. Nestler

    Epigenetic mechanisms of drug addiction

    Neuropharmacology

    (2014)
  • M. Rebucci et al.

    Molecular aspects of cancer cell resistance to chemotherapy

    Biochem. Pharmacol.

    (2013)
  • S.V. Sharma

    A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations

    Cell

    (2010)
  • P.G. Richardson

    PANORAMA 2: panobinostat in combination with bortezomib and dexamethasone in patients with relapsed and bortezomib-refractory myeloma

    Blood

    (2013)
  • A. Mai

    Discovery of uracil-based histone deacetylase inhibitors able to reduce acquired antifungal resistance and trailing growth in Candida albicans

    Bioorg. Med. Chem. Lett.

    (2007)
  • P. Sharma

    An epigenetic antimalarial resistance mechanism involving parasite genes linked to nutrient uptake

    J. Biol. Chem.

    (2013)
  • B. Chen

    GPx3 promoter hypermethylation is a frequent event in human cancer and is associated with tumorigenesis and chemotherapy response

    Cancer Lett.

    (2011)
  • M. Candelaria

    A phase II study of epigenetic therapy with hydralazine and magnesium valproate to overcome chemotherapy resistance in refractory solid tumors

    Ann. Oncol.

    (2007)
  • E. Cervera

    Epigenetic therapy with hydralazine and magnesium valproate reverses imatinib resistance in patients with chronic myeloid leukemia

    Clin. Lymphoma Myeloma Leuk.

    (2012)
  • A. Younes

    Mocetinostat for relapsed classical Hodgkin's lymphoma: an open-label, single-arm, phase 2 trial

    Lancet Oncol.

    (2011)
  • A.R. Shuldiner

    The Pharmacogenomics Research Network Translational Pharmacogenetics Program: overcoming challenges of real-world implementation

    Clin. Pharmacol. Ther.

    (2013)
  • S.C. Su

    Digging up the human genome: current progress in deciphering adverse drug reactions

    Biomed. Res. Int.

    (2014)
  • C.H. Arrowsmith

    Epigenetic protein families: a new frontier for drug discovery

    Nat Rev. Drug Discov.

    (2012)
  • W.D. Chen

    Neonatal activation of the nuclear receptor CAR results in epigenetic memory and permanent change of drug metabolism in mouse liver

    Hepatology

    (2012)
  • J.P. Thomson

    Dynamic changes in 5-hydroxymethylation signatures underpin early and late events in drug exposed liver

    Nucleic Acids Res.

    (2013)
  • R.A. Irizarry

    The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores

    Nat. Genet.

    (2009)
  • L. Burger

    Identification of active regulatory regions from DNA methylation data

    Nucleic Acids Res.

    (2013)
  • V.M. Marx

    Stereoselective access to Z and E macrocycles by ruthenium-catalyzed Z-selective ring-closing metathesis and ethenolysis

    J. Am. Chem. Soc.

    (2013)
  • M.B. Stadler

    DNA-binding factors shape the mouse methylome at distal regulatory regions

    Nature

    (2011)
  • N. Sasai et al.

    Many paths to one goal? The proteins that recognize methylated DNA in eukaryotes

    Int. J. Dev. Biol.

    (2009)
  • E.W. Tobi

    DNA methylation differences after exposure to prenatal famine are common and timing- and sex-specific

    Hum. Mol. Genet.

    (2009)
  • R.M. Kohli et al.

    TET enzymes, TDG and the dynamics of DNA demethylation

    Nature

    (2013)
  • G.P. Pfeifer

    5-Hydroxymethylcytosine and its potential roles in development and cancer

    Epigenet Chromatin

    (2013)
  • M. Ivanov

    Ontogeny, distribution and potential roles of 5-hydroxymethylcytosine in human liver function

    Genome Biol.

    (2013)
  • M.J. Booth

    Quantitative sequencing of 5-methylcytosine and 5-hydroxymethylcytosine at single-base resolution

    Science

    (2012)
  • A.J. Bannister et al.

    Regulation of chromatin by histone modifications

    Cell Res.

    (2011)
  • K.H. Hansen et al.

    Epigenetic inheritance through self-recruitment of the polycomb repressive complex 2

    Epigenetics

    (2009)

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