H epatitis B, caused by hepatitis B virus (HBV) infection, is very common in Asia, Africa, and the Middle East. It is estimated that there are 280 million carriers worldwide, representing more than 5% of the global population. Chronic infection with HBV is a major risk factor for the development of hepatocellular carcinoma (HCC); however, the mechanism by which HBV induces events leading to HCC has not been clearly elucidated. The HBV genome consists of four overlapping open reading frames encoding DNA polymerase, surface antigen, core protein, and a regulatory X protein [hepatitis B virus X protein (HBx)].

Metastasis-associated protein 1 (MTA1) is a component of the nucleosome remodeling and histone deacetylase (HDAC) complex, which plays an important role in progression of breast cancer. Although MTA1 is known as a repressor of the transactivation function of estrogen receptor a (ERa), its involvement in the epigenetic control of transcription of the ERa gene ESR1 has not been studied. Here, we show that silencing of MTA1 reduced the level of expression of ERa in ERa-positive cells but increased it in ERa-negative cells. In both MCF7 and MDA-MB-231, MTA1 was recruited to the region þ146 to þ461 bp downstream of the transcription start site of ESR1 (ERpro315). Proteomics analysis of the MTA1 complex that was pulled down by an oligonucleotide encoding ERpro315 revealed that the transcription factor AP-2g (TFAP2C) and the IFN-g-inducible protein 16 (IFI16) were components of the complex. Interestingly, in MCF7, TFAP2C activated the reporter encoding ERpro315 and the level of ERa mRNA. By contrast, in MDA-MB-231, IFI16 repressed the promoter activity and silencing of MTA1 increased expression of ERa. Importantly, class II HDACs are involved in the MTA1-mediated differential regulation of ERa. Finally, an MDA-MB-231-derived cell line that stably expressed shIFI16 or shMTA1 was more susceptible to tamoxifen-induced growth inhibition in in vitro and in vivo experiments. Taken together, our findings suggest that the MTA1-TFAP2C or the MTA1-IFI16 complex may contribute to the epigenetic regulation of ESR1 expression in breast cancer and may determine the chemosensitivity of tumors to tamoxifen therapy in patients with breast cancer. Cancer Res; 74(5); 1484-94. Ó2014 AACR.

Objective-Hypoxia-inducible factor 1␣ (HIF-1␣) is primarily involved in the adapting of cells to changes in oxygen levels, which is essential for normal vascular function. Recently, physiological roles for retinoic acid-related orphan receptor ␣ (ROR␣) have been implicated in cardiovascular diseases such as atherosclerosis. In this study, we have investigated the potential roles of ROR␣ in the hypoxia signaling pathway in connection with activation of HIF-1␣. Key Words: ROR␣ Ⅲ hypoxia Ⅲ HIF-1␣ Ⅲ melatonin Ⅲ vascular endothelial growth factor R etinoic acid receptor-related orphan receptor ␣ (ROR␣; NR1F1) is a member of the steroid/thyroid hormone receptor superfamily of transcriptional factors and is closely related to the retinoic acid receptors. 1,2 ROR␣ exists in 4 isoforms, ROR␣1, ROR␣2, ROR␣3, and ROR␣4 (also known as RZR␣), which are generated by a combination of alternative promoter use and exon splicing of the RORA gene. 2 These isoforms comprise a common DNA-binding domain (DBD) and a putative ligand-binding domain (LBD), but differ by their N-terminal sequences. 3 Melatonin and synthetic thiazolidine diones have been shown to transactivate ROR␣, although these observations need to be clarified. 4,5 Recently, analysis of the crystal structure of the ligand-binding domain of ROR␣ revealed that a ligand is present in the binding pocket. This was identified as cholesterol, suggesting that plasma and intracellular levels of cholesterol may be important in the regulation of transcriptional activity for ROR␣. 6,7 ROR␣ usually binds as a monomer to a ROR response element (RORE) consisting of a half site core AGGTCA motif or as a homodimer to a direct repeat of the core motif separated by 2 base pairs. 1 Putative ROREs have been identified in the promoters, such as human fibrinogen ␤, Apo A-V, Apo A-I, Apo C-III, PPAR␥, and RevErb␣, which may suggest a role of this receptor in lipid metabolism and cardiovascular physiology. 8 -12 However, little is known regarding the internal and external stimuli that regulate the RORA gene expression.ROR␣ functions have been studied with the help of the staggerer (sg/sg) mutant mouse. A spontaneous mutation in the ligand-binding domain induces a frameshift that results in a protein truncated in its C terminus and generates the staggerer phenotype. 13 These animals experience severe cerebellar ataxia caused by massive neurodegeneration of Purkinje cells. 14 Moreover, the phenotype of these mice revealed that ROR␣ is crucially involved in regulating the inflammatory and immune responses and lipid metabolism, which are closely related to vascular disorders such as atherosclerosis. 15,16 In the staggerer mice, angiogenesis is enhanced markedly after ischemia induced by the ligation of the femoral artery. 17 In the vascular system, ROR␣ mRNAs have been detected in human smooth muscle cells (SMCs), endothelial cells (ECs), as well as mammary arteries. 16,18 ROR␣ expression level is significantly decreased in human atherosclerotic plaques, whereas increased expression is observed a...

Differentiation of sebocytes is strongly associated with enhanced lipid synthesis and accumulation in the cells. Liver X receptors (LXRs) are members of the nuclear receptor superfamily, which play a critical role in cholesterol homeostasis and lipid metabolism. We examined whether LXRalpha regulated lipid synthesis in the immortalized human sebaceous gland cell line SZ95. When the SZ95 sebocytes were treated with the ligand of LXR such as TO901317 or 22(R)-hydroxycholesterol, lipid droplets were accumulated in the majority of cells when examined by Oil Red O staining. The expression of the known LXR targets, such as fatty acid synthase and sterol regulatory-binding protein-1, was induced by TO901317. TO901317 treatment increased expression of LXRalpha but not that of LXRbeta. Transfection of antisense LXRalpha significantly decreased TO901317-induced target gene expression and lipid droplet accumulation, suggesting a major role of LXRalpha in differentiation of sebocytes. Further, TO901317 decreased the expression of cyclooxygenase-2 and inducible nitric oxide synthase that was induced by lipopolysaccharide treatment. Together, these results indicate that important roles of LXRalpha in differentiation and inflammatory signaling in sebaceous glands. Thus, we suggest that LXR ligands could provide a new class of therapeutic agents for sebaceous gland-associated disorders such as seborrhea and acne.