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The AAPS Journal

, Volume 16, Issue 1, pp 151–163 | Cite as

Plant Phytochemicals as Epigenetic Modulators: Role in Cancer Chemoprevention

  • Vijay S. Thakur
  • Gauri Deb
  • Melissa A. Babcook
  • Sanjay GuptaEmail author
Review Article Theme: Natural Products Drug Discovery in Cancer Prevention

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.

KEY WORDS

cancer chemoprevention dietary agents DNA methylation epigenetics histone modification microRNA 

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

Notes

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.

Conflict of Interest

The authors have no competing interest.

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Copyright information

© American Association of Pharmaceutical Scientists 2013

Authors and Affiliations

  • Vijay S. Thakur
    • 1
  • Gauri Deb
    • 1
    • 2
  • Melissa A. Babcook
    • 1
    • 3
  • Sanjay Gupta
    • 1
    • 3
    • 4
    Email author
  1. 1.Department of UrologyCase Western Reserve University, University Hospitals Case Medical CenterClevelandUSA
  2. 2.Department of BiotechnologyIndian Institute of TechnologyGuwahatiIndia
  3. 3.Department of NutritionCase Western Reserve UniversityClevelandUSA
  4. 4.Division of General Medical SciencesCase Comprehensive Cancer CenterClevelandUSA

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