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Plant Phytochemicals as Epigenetic Modulators: Role in Cancer Chemoprevention

  • Review Article
  • Theme: Natural Products Drug Discovery in Cancer Prevention
  • Published:
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Abstract

In recent years, “nutri-epigenetics,” which focuses on the influence of dietary agents on epigenetic mechanism(s), has emerged as an exciting novel area in epigenetics research. Targeting of aberrant epigenetic modifications has gained considerable attention in cancer chemoprevention research because, unlike genetic changes, epigenetic alterations are reversible and occur during early carcinogenesis. Aberrant epigenetic mechanisms, such as promoter DNA methylation, histone modifications, and miRNA-mediated post-transcriptional alterations, can silence critical tumor suppressor genes, such as transcription factors, cell cycle regulators, nuclear receptors, signal transducers, and apoptosis-inducing and DNA repair gene products, and ultimately contribute to carcinogenesis. In an effort to identify and develop anticancer agents which cause minimal harm to normal cells while effectively killing cancer cells, a number of naturally occurring phytochemicals in food and medicinal plants have been investigated. This review highlights the potential role of plant-derived phytochemicals in targeting epigenetic alterations that occur during carcinogenesis, by modulating the activity or expression of DNA methyltransferases, histone modifying enzymes, and miRNAs. We present in detail the epigenetic mode of action of various phytochemicals and discuss their potential as safe and clinically useful chemopreventive strategies.

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Abbreviations

Akt:

v-akt murine thymoma viral oncogene homolog 1

AM:

Allyl mercaptan

AP-1:

Activator Protein-1

AR:

Androgen receptor

Bax:

BCL2-associated X protein

Bcl2:

B-cell CLL/lymphoma 2

Bcl-xL:

B-cell lymphoma-extra large

Bmi-1:

B-cell-specific Moloney murine leukemia virus integration site 1

BRCA1:

Breast cancer 1, early onset

CBP:

CREB-binding protein

CCND2:

Cyclin D2

Cdc25A:

Cell division cycle 25 homolog A

Cdk:

Cyclin-dependent kinase

c-Kit:

v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog

COMT:

Catechol-O-methyltransferase

COX-2:

Cyclooxygenase-2

CYLD:

Cylindromatosis (turban tumor syndrome)

DADS:

Diallyl disulfide

DAS:

Diallyl sulfide

DATS:

Diallyl trisulfide

DHFR:

Dihydrofolate reductase

DMBA:

7,12-dimethylbenz(a)anthracene

DNMT:

DNA methyltransferase

DNMT-3L:

DNA (cytosine-5)-methyltransferase 3-like

E2F:

E2F transcription factor

EC:

[−]-epicatechin

ECG:

[−]-epicatechin-3-gallate

EGC:

[−]-epigallocatechin

EGCG:

[−]-epigallocatechin-3-gallate

EGFR:

Epidermal growth factor receptor

ER:

Estrogen receptor

ERβ:

Estrogen receptor beta

ERBB2:

Human epidermal growth factor receptor 2

ERα:

Estrogen receptor alpha

EZH-2:

Enhancer of zeste homolog 2

FOXO3a:

Forkhead box protein O3

GCN5:

SAGA complex histone acetyltransferase catalytic subunit Gcn5

GSTP1:

Glutathione-S-transferase pi 1

HATs:

Histone acetyl transferases

HDACs:

Histone deacetylases

HER-2:

Human epidermal growth factor receptor 2

HIF-1 α:

Hypoxia inducible factor 1, alpha subunit

HKMTs:

Histone lysine methyltransferases

hMLH1:

Human mutL homolog 1

HOX family proteins:

Homeobox family proteins

HSP90:

Heat shock protein 90

hTERT:

Human telomerase reverse transcriptase

IP-10:

TNF-induced interferon-gamma-inducible protein 10

K:

Lysine

LEF:

Lymphoid enhancer factor

MBD:

Methylated DNA binding domain proteins

MCL1:

Induced myeloid leukemia cell differentiation protein Mcl-1

MCM-2:

Minichromosome maintenance gene

MGMT-O(6):

Methylguanine-DNA methyltransferase

MIP-2:

Macrophage inflammatory protein 2

miRNA:

MicroRNA

MTA-2:

Metastasis associated 1 family member 2

NF-κB:

Nuclear factor kappa-light-chain-enhancer of activated B cells

Notch1:

Notch homolog 1, translocation-associated (Drosophila)

OSCs:

Organosulfur compounds

p16INK4a:

Cyclin-dependent kinase 4 inhibitor A

p21waf1/cip1:

Cyclin-dependent kinase inhibitor 1A

p53:

Tumor protein 53

PARP:

Poly ADP-ribose polymerase

PCAF:

K(lysine) acetyltransferase 2B

PcG:

Polycomb group proteins

PDCD4:

Programmed cell death 4

PEITC:

Phenethyl isothiocyanate

PRPS1:

Phosphoribosyl pyrophosphate synthetase 1

PTEN:

Phosphatase and tensin homolog deleted on chromosome 10

RARβ2:

Retinoic acid receptor, beta 2

R:

Arginine

RAS:

Rat sarcoma transforming oncogene

RASSF1A:

RAS association domain family 1A

RXR alpha:

Retinoid X receptor, alpha

SAH:

S-adenosyl-L-homocysteine

SAM:

S-adenosyl methionine

SAMC:

S-allylmercaptocysteine

SIRT1:

Sirtuin (silent mating type information regulation 2 homolog) 1

SLC16A1:

Solute carrier family 16, member 1

SNX19:

Sorting nexin-19

Sp1:

Transcription Factor Sp1

TGFBR2:

Transforming growth factor, beta receptor II

TGF-β:

Transforming growth factor, beta

TTK:

Phosphotyrosine picked threonine-protein kinase

VEGF:

Vascular endothelial cell growth factor

ZBTB10:

Zinc finger and BTB domain containing 10

ZEB1:

Zinc finger E-box binding homeobox 1

ZNF513:

Zinc finger protein 513

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ACKNOWLEDGMENTS

The original work from author’s laboratory outlined in this review was supported by United States Public Health Service Grants RO1CA108512, RO1CA115491 and RO1AT002709. We acknowledge Shyama Prasad Mukherjee (SPM) fellowship provided to GD by the Council of Scientific and Industrial Research (CSIR), India and Fulbright-Nehru Doctoral and Professional Research fellowship provided by United States—India Educational Foundation (USIEF) for her work in the United States. MAB is supported by NIH 5T32DK007316 Ruth L. Kirschstein Pre-Doctoral Fellowship through the Metabolism Training Program. We apologize to those investigators whose original work could not be cited owing to the space limitations.

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The authors have no competing interest.

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Authors and Affiliations

  1. Department of Urology, Case Western Reserve University, University Hospitals Case Medical Center, 10900 Euclid Avenue, Cleveland, Ohio, 44106, USA

    Vijay S. Thakur, Gauri Deb, Melissa A. Babcook & Sanjay Gupta

  2. Department of Biotechnology, Indian Institute of Technology, Guwahati, Assam, India

    Gauri Deb

  3. Department of Nutrition, Case Western Reserve University, Cleveland, Ohio, USA

    Melissa A. Babcook & Sanjay Gupta

  4. Division of General Medical Sciences, Case Comprehensive Cancer Center, Cleveland, Ohio, USA

    Sanjay Gupta

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  1. Vijay S. Thakur
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  2. Gauri Deb
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  3. Melissa A. Babcook
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  4. Sanjay Gupta
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Correspondence to Sanjay Gupta.

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Guest Editors: Ah-Ng Tony Kong and Chi Chen

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Thakur, V.S., Deb, G., Babcook, M.A. et al. Plant Phytochemicals as Epigenetic Modulators: Role in Cancer Chemoprevention. AAPS J 16, 151–163 (2014). https://doi.org/10.1208/s12248-013-9548-5

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  • DOI: https://doi.org/10.1208/s12248-013-9548-5

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