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Zinc deficiency alters DNA damage response genes in normal human prostate epithelial cells.

ABSTRACT: Zinc is an essential trace element for human health and is a critical component of many proteins and transcription factors involved in DNA damage response and repair. The prostate is known to accumulate high levels of zinc, but levels are markedly decreased with cancer development. We hypothesized that zinc plays a critical role in maintaining DNA integrity in the prostate and zinc deficiency would lead to increased DNA damage and altered DNA damage response mechanisms. To test this hypothesis, the goal of this study was to determine the effects of zinc deficiency on DNA damage and DNA repair mechanisms by examining changes in global gene expression and transcription factor binding abilities in normal prostate epithelial cells (PrEC). Increased single-strand DNA breaks (Comet assay) were observed in PrEC grown in zinc-deficient media compared with cells grown in zinc-adequate media for 7 d. Using Affymetrix HG-U133A gene chips, differential expression of genes involved in cell cycle, apoptosis, transcription, and DNA damage response and repair were identified with low cellular zinc. Among genes involved in DNA damage response and repair, tumor protein p73, MRE11 meiotic recombination 11 homolog A, X-ray repair complementing defective repair in Chinese hamster cells 4, and breast cancer 2, early onset were down-regulated and TP53 was up-regulated. Additionally, western blotting showed increased nuclear p53 protein expression with zinc deficiency. Despite increased p53 gene and nuclear protein expression, there was no significant change in p53 binding activity. Zinc deficiency also induced an increase in binding activity of transcription factors involved in regulating cell proliferation and apoptosis. Thus, zinc deficiency may compromise DNA integrity in the prostate by impairing the function of zinc-containing proteins.

SUBMITTER: Yan M

PROVIDER: S-EPMC4152237 | biostudies-literature | 2008 Apr

REPOSITORIES: biostudies-literature

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Zinc deficiency alters DNA damage response genes in normal human prostate epithelial cells.

Yan Michelle M Song Yang Y Wong Carmen P CP Hardin Karin K Ho Emily E

The Journal of nutrition 20080401 4

Zinc is an essential trace element for human health and is a critical component of many proteins and transcription factors involved in DNA damage response and repair. The prostate is known to accumulate high levels of zinc, but levels are markedly decreased with cancer development. We hypothesized that zinc plays a critical role in maintaining DNA integrity in the prostate and zinc deficiency would lead to increased DNA damage and altered DNA damage response mechanisms. To test this hypothesis, ...[more]

PMID: 18356318

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Project description:Steroid hormone signaling induces vast gene expression programs which necessitate the local formation of transcription factories at regulatory regions and large-scale alterations of the genome architecture to allow communication among distantly related cis-acting regions. This involves major stress at the genomic DNA level. Transcriptionally active regions are generally instable and prone to breakage due to the torsional stress and local depletion of nucleosomes that make DNA more accessible to damaging agents. A dedicated DNA damage response (DDR) is therefore essential to maintain genome integrity at these exposed regions. The DDR is a complex network involving DNA damage sensor proteins, such as the poly(ADP-ribose) polymerase 1 (PARP-1), the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), the ataxia-telangiectasia-mutated (ATM) kinase and the ATM and Rad3-related (ATR) kinase, as central regulators. The tight interplay between the DDR and steroid hormone receptors has been unraveled recently. Several DNA repair factors interact with the androgen and estrogen receptors and support their transcriptional functions. Conversely, both receptors directly control the expression of agents involved in the DDR. Impaired DDR is also exploited by tumors to acquire advantageous mutations. Cancer cells often harbor germline or somatic alterations in DDR genes, and their association with disease outcome and treatment response led to intensive efforts towards identifying selective inhibitors targeting the major players in this process. The PARP-1 inhibitors are now approved for ovarian, breast, and prostate cancer with specific genomic alterations. Additional DDR-targeting agents are being evaluated in clinical studies either as single agents or in combination with treatments eliciting DNA damage (e.g., radiation therapy, including targeted radiotherapy, and chemotherapy) or addressing targets involved in maintenance of genome integrity. Recent preclinical and clinical findings made in addressing DNA repair dysfunction in hormone-dependent and -independent prostate and breast tumors are presented. Importantly, the combination of anti-hormonal therapy with DDR inhibition or with radiation has the potential to enhance efficacy but still needs further investigation.

Dataset Information

Zinc deficiency alters DNA damage response genes in normal human prostate epithelial cells.

Publications

Zinc deficiency alters DNA damage response genes in normal human prostate epithelial cells.

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