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Nutrient-Gene Interactions

Diindolylmethane Alters Gene Expression in Human Keratinocytes In Vitro^{1 ,2}

Timothy H. Carter^*,,**, Kai Liu^*,, Walter Ralph, Jr.^*,, DaZhi Chen^*,, Mei Qi, Saijun Fan^*,, Fang Yuan^,3, Eliot M. Rosen^*,, and Karen J. Auborn^4*,,

^* North Shore-Long Island Jewish Research Institute, Manhasset, NY 11030; Department of Otolaryngology, Long Island Jewish Medical Center, The Long Island Campus of Albert Einstein College of Medicine, New Hyde Park, NY 11040; ^** Biological Sciences, St Johns University, Jamaica, NY 11530; Department of Radiation Oncology, Long Island Jewish Medical Center, The Long Island Campus of Albert Einstein College of Medicine, New Hyde Park, NY 11040; and Developmental and Molecular Biology and Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461

⁴To whom correspondence should be addressed. E-mail: kauborn{at}nshs.edu.

Indole-3-carbinol (I3C) and its dimer 3,3'-diindolylmethane (DIM), obtained from dietary consumption of cruciferous vegetables, have multiple biochemical activities. Both compounds have been effective clinically in treating precancerous lesions of the cervix and laryngeal papillomas, pathologies with a human papillomavirus (HPV) component. Using cDNA microarrays, we examined early changes in gene expression after treatment with 100 µmol/L DIM in C33A and CaSki cervical cancer cells and in an immortalized human epithelial cell line (HaCat), as well as in normal human foreskin keratinocytes (HFK). Multiple analyses were done after treating C33A cells for 6 h; other analyses included 4- and 12-h treatments of C33A and 6-h treatments of CaSki, HaCat and HFK cells. DIM consistently altered the expression of >100 genes at least twofold. Many of the stimulated genes encode transcription factors and proteins involved in signaling, stress response and growth. Results were comparable between transformed cells with and without integrated HPV sequences, and many of the same genes were induced in these cancer-derived cells and in noncancer cells. Eight genes encoding bZip proteins were among the most consistently and robustly induced, including the stress-associated immediate early gene GADD153 (>50 fold in C33A) and nuclear factor-interleukin 6 (NF-IL6), also known as c/EBPß, (>5 fold in C33A), which has been shown to reduce expression of HPV oncogenes. Induction of GADD153, NF-IL6 and ATF3 was confirmed by Western analysis. In functional analyses, DIM not only suppressed transcription of a luciferase gene driven by the HPV11 upstream regulatory region (URR) in C33A, CaSki, HaCat and HFK cells from >2-fold to 37-fold depending on the type of cells, but also reduced endogenous transcription of HPV16 oncogenes to undetectable levels in CaSki cells as determined by an RNase protection assay. Ectopic expression of GADD153 or NF-IL6 suppressed transcription in a dose-dependent manner driven by the HPV11 URR in C33A, CaSki, HaCat and HFK cells. These results identify unexpected ways in which dietary I3C and DIM invoke cellular responses and are consistent with a potential antiviral effect of DIM on keratinocytes, but they do not explain the differential sensitivity of transformed keratinocytes to apoptosis by DIM.

KEY WORDS: • diindolylmethane • apoptosis • humans • DNA microarray • human papilloma virus

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