Improved understanding of the molecular mechanisms by which small-molecule inhibitors of histone deacetylases (HDAC) induce programs, such as cellular differentiation and apoptosis, would undoubtedly assist their clinical development as anticancer agents. As modulators of gene transcript levels, HDAC inhibitors (HDACi) typically affect only 5% to 10% of actively transcribed genes with approximately as many mRNA transcripts being up-regulated as down-regulated. Using microRNA (miRNA) array analysis, we report rapid alteration of miRNA levels in response to the potent hydroxamic acid HDACi LAQ824 in the breast cancer cell line SKBr3. Within 5 hours of exposure to a proapoptotic dose of LAQ824, significant changes were measured in 40% of the >60 different miRNA species expressed in SKBr3 cells with 22 miRNA species down-regulated and 5 miRNAs upregulated. To explore a potential functional link between HDACi induced mRNA up-regulation and miRNA downregulation, antisense experiments were done against miR-27a and miR-27b, both abundantly expressed and down-regulated in SKBr3 cells by LAQ824. Correlating a set of genes previously determined by cDNA array analysis to be rapidly up-regulated by LAQ824 in SKBr3 with a database of potential 3Vuntrans-lated region miRNA binding elements, two genes containing putative miR-27 anchor elements were identified as transcriptionally up-regulated following miR-27 antisense transfection, ZBTB10/RINZF, a Sp1 repressor, and RYBP/DEDAF, an apoptotic facilitator. These findings emphasize the importance of post-transcriptional mRNA regulation by HDACi in addition to their established effects on promoter-driven gene expression. (Cancer Res 2006; 66(3): 1277-81)
The objective of this study was to further establish and confirm the relationship of adipose mitochondrial biogenesis in diabetes/obesity and the effects of rosiglitazone (RSG), a peroxisome proliferator-activated receptor (PPAR) ␥ agonist, by systematically analyzing mitochondrial gene expression and function in two mouse models of obesity and type 2 diabetes. Using microarray technology, adipose mitochondrial gene transcription was studied in db/db, high-fat diet-fed C57BL/6 (HFD) and respective control mice with or without RSG treatment. The findings were extended using mitochondrial staining, DNA quantification, and measurements of citrate synthase activity. In db/db and HFD mice, gene transcripts associated with mitochondrial ATP production, energy uncoupling, mitochondrial ribosomal proteins, outer and inner membrane translocases, and mitochondrial heat-shock proteins were decreased in abundance, compared with db/؉ and standardfat diet-fed control mice, respectively. RSG dose-dependently increased these transcripts in both db/db and HFD mice and induced transcription of mitochondrial structural proteins and cellular antioxidant enzymes responsible for removal of reactive oxygen species generated by increased mitochondrial activity. Transcription factors, including PPAR coactivator (PGC)-1, PGC-1␣, estrogen-related receptor ␣, and PPAR␣, were suppressed in both models and induced by RSG. The effects of RSG on adipose mitochondrial genes were confirmed by quantitative RT-PCR and further supported by mitochondrial staining, mitochondrial DNA quantification, and citrate synthase activity. Adipose mitochondrial biogenesis was overwhelmingly suppressed in both mouse models of diabetes/obesity and globally induced by RSG. These findings suggest an important role of adipose mitochondria in diabetes/obesity and the potential for new treatment approaches targeting adipose mitochondria. Diabetes 56:1751-1760, 2007 P eroxisome proliferator-activated receptor (PPAR) ␥ agonists, including rosiglitazone (RSG), are effective drugs for the treatment of type 2 diabetes. It is well established that RSG induces adipogenesis and causes body-wide lipid repartitioning by increasing adipose triglyceride content, thereby lowering free fatty acids, glycerol, triglycerides, and glucose in the circulation, which is associated with increased insulin sensitivity of the liver, muscle, and other organs. Critical to this process, adipose tissue, which highly expresses PPAR␥, serves not only as a lipid storage depot but also as an endocrine organ producing adipokines that regulate the activity of other tissues (rev. in 1,2).There has been growing interest in exploring the involvement of adipose mitochondria in the regulation of whole-body energy homeostasis (3-9). Recent studies suggest that diabetes/obesity is accompanied by a decrease in the expression of adipose mitochondrial genes in ob/ob mice (8) and impaired adipose mitochondria in db/db mice (9) and that the compromised mitochondrial conditions in ob/ob and db/db mice were reversi...
Background: Recent studies indicate that microRNAs (miRNAs) are mechanistically involved in the development of various human malignancies, suggesting that they represent a promising new class of cancer biomarkers. However, previously reported methods for measuring miRNA expression consume large amounts of tissue, prohibiting high-throughput miRNA profiling from typically small clinical samples such as excision or core needle biopsies of breast or prostate cancer. Here we describe a novel combination of linear amplification and labeling of miRNA for highly sensitive expression microarray profiling requiring only picogram quantities of purified microRNA.
Epidemiological and prospective studies indicate that comprehensive lifestyle changes may modify the progression of prostate cancer. However, the molecular mechanisms by which improvements in diet and lifestyle might affect the prostate microenvironment are poorly understood. We conducted a pilot study to examine changes in prostate gene expression in a unique population of men with low-risk prostate cancer who declined immediate surgery, hormonal therapy, or radiation and participated in an intensive nutrition and lifestyle intervention while undergoing careful surveillance for tumor progression. Consistent with previous studies, significant improvements in weight, abdominal obesity, blood pressure, and lipid profile were observed (all P < 0.05), and surveillance of low-risk patients was safe. Gene expression profiles were obtained from 30 participants, pairing RNA samples from control prostate needle biopsy taken before intervention to RNA from the same patient's 3-month postintervention biopsy. Quantitative real-time PCR was used to validate array observations for selected transcripts. Two-class paired analysis of global gene expression using significance analysis of microarrays detected 48 up-regulated and 453 down-regulated transcripts after the intervention. Pathway analysis identified significant modulation of biological processes that have critical roles in tumorigenesis, including protein metabolism and modification, intracellular protein traffic, and protein phosphorylation (all P < 0.05). Intensive nutrition and lifestyle changes may modulate gene expression in the prostate. Understanding the prostate molecular response to comprehensive lifestyle changes may strengthen efforts to develop effective prevention and treatment. Larger clinical trials are warranted to confirm the results of this pilot study.exercise ͉ lifestyle changes ͉ prostate cancer ͉ SHOC2 ͉ stress management E pidemiological evidence (1, 2) and migrant studies (3) indicate that the incidence of clinically significant prostate cancer is much lower in parts of the world where people eat a predominantly low-fat, plant-based diet. We (4, 5) and others (6) have shown previously that diet and lifestyle interventions in men with earlystage prostate cancer decrease prostate-specific antigen (PSA) and decrease the rate of PSA increase. These studies provided some evidence that comprehensive lifestyle changes may have therapeutic potential in early prostate cancers. However, although these interventions are associated with decreased circulating insulin-like growth factor 1 (IGF1) (7), and although serum from men after intervention has reduced the ability to stimulate prostate cell-line growth in vitro (4), the actual molecular effects of these interventions in prostate tissue have not been previously examined.Many men with indolent prostate cancers detected by PSA screening will not exhibit disease progression during their lifetime; their treatment and associated side effects are unnecessary (8). We report here the results of the Gene Expressio...
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