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Role of xenobiotic metabolism in cancer: involvement of transcriptional and miRNA regulation of P450s

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Abstract

Cytochrome P450 enzymes (P450s) are important targets in cancer, due to their role in xenobiotic metabolism. Since P450s are the “bridges” between the environment and our body, their function can be linked in many ways to carcinogenesis: they activate dietary and environmental components to ultimate carcinogens (i), the cancer tissue maintains its drug resistance with altered expression of P450s (ii), P450s metabolize (sometimes activate) drugs used for cancer treatment (iii) and they are potential targets for anticancer therapy (iiii). These highly polymorphic enzymes are regulated at multiple molecular levels. Regulation is as important as genetic difference in the existing individual variability in P450 activity. In this review, examples of the transcriptional (DNA methylation, histone modification, modulation by xenosensors) and post-transcriptional (miRNA) regulation will be presented and thereby introduce potential molecular targets at which the metabolism of anticancer drugs, the elimination of cancerogenes or the progress of carcinogenesis could be affected.

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Abbreviations

ADPF:

AHR degradation promoting factor

AHR:

Aromatic hydrocarbon receptor

AHRR:

Aromatic hydrocarbon receptor repressor

ARNT:

Aromatic hydrocarbon receptor nuclear translocator

ARE:

Antioxidant response element

ASC2:

Activating signal cointegrator 2

B[a]P:

Benzo[a]pyrene

CAR:

Constitutive androstane receptor

CREBBP:

CREB-binding protein

DNMT:

DNA methyltransferase

ER:

Estrogen receptor

FOXO:

Forkhead box O

GR:

Glucocorticoid receptor

GRIP1:

Glucocorticoid receptor interacting protein 1

HDAC1:

Histone deacetylase-1

HIF-1:

Hypoxia induced factor

HNF-4α:

Hepatocyte nuclear factor

KEAP-1:

Kelch-like ECH-associated protein 1

3-MC:

3-Methylcholantrene

NcoR:

Nuclear receptor corepressor

NF-κb:

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

NRF2:

NF-E2-related factor 2

PRMT1:

Arginine methyltransferase 1

PXR:

Pregnane X receptor

RXR:

Retinoid X receptor

SMC-1:

Structural maintenance of chromosomes 1-like 1

SRC-1:

Steroid receptor coactivator-1

SMRT:

Silencing mediator for retinoid and thyroid receptor

TUF2:

Transcriptional intermediary factor 2

VDR:

Vitamin D receptor

XAP2:

Immunophillin like X protein XAP2

XAR:

Xenobiotic activated receptors

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Authors and Affiliations

  1. Department of Genetics, Cell- and Immunobiology, Faculty of Medicine, Semmelweis University, PO Box 370, Budapest, 1445, Hungary

    Viola Tamási & András Falus

  2. Chemical Research Center, Hungarian Academy of Sciences, PO Box 17, 1525, Budapest, Hungary

    Katalin Monostory

  3. Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, KY, 40292, USA

    Russell A. Prough

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  1. Viola Tamási
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  2. Katalin Monostory
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  4. András Falus
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Correspondence to Viola Tamási.

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Tamási, V., Monostory, K., Prough, R.A. et al. Role of xenobiotic metabolism in cancer: involvement of transcriptional and miRNA regulation of P450s. Cell. Mol. Life Sci. 68, 1131–1146 (2011). https://doi.org/10.1007/s00018-010-0600-7

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