The chromatin remodeling complex SWI/SNF is an important epigenetic regulator that includes one Brm or BRG1 molecule as catalytic subunit. Brm and BRG1 do not function identically, so this complex can regulate gene expression either positively or negatively, depending on the promoter to which it is recruited. Notably, Brm attenuation due to posttranscription suppression occurs often in human tumor cells, in which this event contributes to their oncogenic potential. Here, we report that the 3 0 -untranslated region of Brm mRNA has two sites that are efficiently targeted by the microRNAs miR-199a-5p and -3p, revealing a novel mechanism for modulation of Brm-type SWI/SNF activity. Computational mapping of the putative promoter region of miR-199a-2 (miPPR-199a-2) has defined it as the major contributing genetic locus for miR-199a-5p and-3p production in these tumor cell lines. We validated this predicted region by direct promoter analysis to confirm that Egr1 is a strong positive regulator of the miR-199a-2 gene. Importantly, we also showed that Egr1, miR-199a-5p, and miR-199a-3p are expressed at high levels in Brm-deficient tumor cell lines but only marginally in Brm-expressing tumor cells. Finally, we also obtained evidence that Brm negatively regulates Egr1. Together, our results reveal that miR-199a and Brm form a double-negative feedback loop through Egr1, leading to the generation of these two distinct cell types during carcinogenesis. This mechanism may offer a partial explanation for why miR-199a-5p and -3p have been reported to be either upregulated or downregulated in a variety of tumors. Cancer Res; 71(5); 1680-9. Ó2010 AACR.

Rationale: Association of habitual coffee consumption with coronary heart disease morbidity and mortality has not been established. We hypothesized that coffee may enhance reverse cholesterol transport (RCT) as the antiatherogenic properties of high-density lipoprotein (HDL). Objective: This study was to investigate whether the phenolic acids of coffee and coffee regulates RCT from macrophages in vitro, ex vivo and in vivo. Methods and Results: Caffeic acid and ferulic acid, the major phenolic acids of coffee, enhanced cholesterol efflux from THP-1 macrophages mediated by HDL, but not apoA-I. Furthermore, these phenolic acids increased both the mRNA and protein levels of ATP-binding cassette transporter (ABC)G1 and scavenger receptor class B type I (SR-BI), but not ABCA1. Eight healthy volunteers were recruited for the ex vivo study, and blood samples were taken before and 30 minutes after consumption of coffee or water in a crossover study. The mRNA as well as protein levels of ABCG1, SR-BI, and cholesterol efflux by HDL were increased in the macrophages differentiated under autologous sera obtained after coffee consumption compared to baseline sera. Finally, effects of coffee and phenolic acid on in vivo RCT were assessed by intraperitoneally injecting Key Words: HDL cholesterol Ⅲ efflux Ⅲ coffee Ⅲ phenolic acid H igh-density lipoproteins (HDLs) have been shown to be inversely associated with the risk of atherosclerotic cardiovascular disease (CVD) 1,2 and thus considered as antiatherogenic lipoproteins. Among antiatherogenic mechanisms including beneficial effects on inflammation, impaired endothelial function or hypercoagulation, HDL exerts the antiatherogenic property primarily by facilitating the efflux of cholesterol from peripheral tissues and transport it back to the liver in a process called reverse cholesterol transport (RCT). A major breakthrough in the understanding of the mechanism of RCT came with the discovery of the ATP binding cassette transporter (ABC)A1. Lipid-poor apolipoprotein (apo)A-I contributes to ABCA1-mediated cholesterol efflux from cells, but not HDL. 3,4 Another ABC transporter, ABCG1, is also involved in the cholesterol efflux from macrophages mediated by HDL, but not apoA-I. 4,5 Scavenger receptor class B type I (SR-BI) is also known to promote HDL-mediated cellular cholesterol efflux. 6 Furthermore, the pivotal roles of these molecules on intracellular cholesterol homeostasis, associated with reverse cholesterol transport, have also been confirmed by animal studies where deletions of ABCA1, 7 ABCG1, 8 and SR-BI 9 in macrophages accelerated the development of atherosclerosis.Coffee is among the most widely consumed beverages worldwide. The relationship between coffee consumption and the incidence of CVD has been studied extensively. 10 -12 In addition, a recent study reported that regular coffee consumption might be associated with a decreased cardiovascular mortality rate. 13 Coffee beans are known to be abundant in antioxidant phenolic acids, chlorogenic acid. Indeed, Xia M et...