The dietary isothiocyanate sulforaphane modulates gene expression and alternative gene splicing in a PTEN null preclinical murine model of prostate cancer.
BACKGROUND
Dietary or therapeutic interventions to counteract the loss of PTEN expression could contribute to the prevention of prostate carcinogenesis or reduce the rate of cancer progression. In this study, we investigate the interaction between sulforaphane, a dietary isothiocyanate derived from broccoli, PTEN expression and gene expression in pre malignant prostate tissue.


RESULTS
We initially describe heterogeneity in expression of PTEN in non-malignant prostate tissue of men deemed to be at risk of prostate cancer. We subsequently use the mouse prostate-specific PTEN deletion model, to show that sulforaphane suppresses transcriptional changes induced by PTEN deletion and induces additional changes in gene expression associated with cell cycle arrest and apoptosis in PTEN null tissue, but has no effect on transcription in wild type tissue. Comparative analyses of changes in gene expression in mouse and human prostate tissue indicate that similar changes can be induced in humans with a broccoli-rich diet. Global analyses of exon expression demonstrated that sulforaphane interacts with PTEN deletion to modulate alternative gene splicing, illustrated through a more detailed analysis of DMBT1 splicing.


CONCLUSIONS
To our knowledge, this is the first report of how diet may perturb changes in transcription induced by PTEN deletion, and the effects of diet on global patterns of alternative gene splicing. The study exemplifies the complex interaction between diet, genotype and gene expression, and the multiple modes of action of small bioactive dietary components.
Traka
Maria H
MH
Plant Natural Products and Health Programme, Institute of Food Research, Norwich, NR4 7UA, UK.
Spinks
Caroline A
CA
Doleman
Joanne F
JF
Melchini
Antonietta
A
Ball
Richard Y
RY
Mills
Robert D
RD
Mithen
Richard F
RF
D017398:Alternative Splicing / Q000187:drug effects*; D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D004032:Diet; D004195:Disease Models, Animal; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects*; D017879:Isothiocyanates; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D013454:Sulfoxides; D013861:Thiocyanates / Q000008:administration & dosage / Q000494:pharmacology*
D017879:Isothiocyanates; D013454:Sulfoxides; D013861:Thiocyanates; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; C016766:sulforaphane