Farnesoid X receptor (FXR) is a receptor for bile acids and plays an important role in the regulation of bile acid metabolism in the liver. Although FXR has been shown to affect hepatocarcinogenesis through both direct and indirect mechanisms, potential roles of FXR in epithelial–mesenchymal transition (EMT) in hepatocellular carcinoma (HCC) remain unclear. We examined the effect of several FXR ligands on EMT-related morphological changes in HCC cell lines, such as HuH-7 and Hep3B cells. FXR agonists (chenodeoxycholic acid, GW4064, and obeticholic acid)—but not an antagonist (guggulsterone)—induced actin polymerization and expression of N-cadherin and phosphorylated focal adhesion kinase, although they were less effective than transforming growth factor β (TGF-β). FXR agonist treatment enhanced TGF-β-induced EMT morphologic changes and FXR antagonist inhibited the effect of TGF-β. Thus, FXR activation enhances EMT in HCC and FXR antagonists may be EMT-suppressing drug candidates.

PPARγ regulates glucose and lipid metabolism, immunity, and cellular growth and differentiation. Thiazolidinediones (TZDs) are synthetic PPARγ ligands that are used in the treatment of type 2 diabetes. However, TZDs can cause adverse effects, such as increased risks of heart failure, bone fractures and bladder cancer. PPARγ has a large ligand-binding pocket, which makes it possible to develop a variety of PPARγ ligands, leading to patents on their therapeutic applications. We summarize recent patent activity regarding PPARγ ligands and their therapeutic applications from 2008. Pharmacologic methods to increase PPARγ expression and to decrease PPARγ adverse effects by combining PPARγ ligands with other drugs are also reviewed. In addition to novel PPARγ ligands that exhibit selective therapeutic activity without adverse effects, such as bone loss, fluid retention or weight gain, methods for the combination of PPARγ ligands and other compounds have been claimed to decrease adverse effects and/or to enhance targeted effects. Combination therapy is useful but has the potential risk of unexpected adverse effects. Patent applications for expanding clinical application of PPARγ ligands to non-metabolic diseases, such as neurological and inflammatory diseases, and to skin whitening have been filed, and future studies are needed to elucidate the underlying mechanisms.

The Dgcr14/Es2 gene is located in a chromosomal region the loss of which has been associated with DiGeorge syndrome, a cause of immunodeficiency, heart defects and skeletal abnormalities. However, the role of DGCR14 protein remains to be elucidated. Here, I found that DGCR14 protein acts as a co-activator of RORγt in T_H17 cells. Biochemical purification of the RORγ co-regulator complex allowed us to identify the associated DGCR14 protein by MALDI-TOF/MS. Overexpression of Dgcr14 mRNA enhanced RORγt-mediated transcriptional activity and facilitated T_H17 cell differentiation. Furthermore, knockdown of Dgcr14 reduced Il17a mRNA expression. I also found that DGCR14 associated with ribosomal S6 kinase 2 (RSK2, also called RpS6ka3) and BAZ1B, both of which were recruited to the Il17a promoter during T_H17 cell differentiation. Knockdown of Baz1b or RpS6ka3 also reduced Il17a mRNA expression and Baz1b knockdown increased transcriptional suppressive histone marks (histone H3K9me3) on the Il17a promoter. My findings showed the regulatory roles of DGCR14, RSK2 and BAZ1B in transcriptional regulation of Il17a mRNA during T_H17 cell differentiation.

Ess2, also known as Dgcr14, is a transcriptional co-regulator of CD4⁺ T cells. Ess2 is located in a chromosomal region, the loss of which has been associated with 22q11.2 deletion syndrome (22q11DS), which causes heart defects, skeletal abnormalities, and immunodeficiency. However, the specific association of Ess2 with 22q11DS remains unclear. To elucidate the role of Ess2 in T-cell development, we generated Ess2 floxed (Ess2^fl/fl) and CD4⁺ T cell–specific Ess2 KO (Ess2^ΔCD4/ΔCD4) mice using the Cre/loxP system. Interestingly, Ess2^ΔCD4/ΔCD4 mice exhibited reduced naïve T-cell numbers in the spleen, while the number of thymocytes (CD4⁻CD8⁻, CD4⁺CD8⁺, CD4⁺CD8⁻, and CD4⁻CD8⁺) in the thymus remained unchanged. Furthermore, Ess2^ΔCD4/ΔCD4 mice had decreased NKT cells and increased γδT cells in the thymus and spleen. A genome-wide expression analysis using RNA-seq revealed that Ess2 deletion alters the expression of many genes in CD4 single-positive thymocytes, including genes related to the immune system and Myc target genes. In addition, Ess2 enhanced the transcriptional activity of c-Myc. Some genes identified as Ess2 targets in mice show expressional correlation with ESS2 in human immune cells. Moreover, Ess2^ΔCD4/ΔCD4 naïve CD4⁺ T cells did not maintain survival in response to IL-7. Our results suggest that Ess2 plays a critical role in post-thymic T-cell survival through the Myc and IL-7 signaling pathways.