Esbensenryberg6794

A greater decrease in 24-h energy expenditure (24EE) during 24h fasting defines a thriftier metabolic phenotype prone to weight gain during overfeeding and resistant to weight loss during caloric restriction. https://www.selleckchem.com/products/kpt-8602.html As the thermogenic response to mild cold exposure (COLD) may similarly characterize this human phenotype identified by acute fasting conditions, we analyzed changes in 24EE and sleeping metabolic rate (SLEEP) in a whole-room indirect calorimeter during 24h fasting at thermoneutrality (24°C) and during energy balance both at thermoneutrality (24°C) and mild cold (19°C) in 20 healthy volunteers (80% male, age 36.6±11.4y, percentage body fat 34.8±10.5%). Greater decrease in 24EE during fasting (thriftier phenotype) was associated with less increase in 24EE during COLD, i.e. less cold-induced thermogenesis. Greater decreases in plasma fibroblast growth factor 21 (FGF21) after 24h fasting and after COLD were highly correlated and associated with greater decreases in SLEEP in both conditions. We conclude that the metabolic responses to short-term fasting and COLD are associated and mediated by the liver-derived hormone FGF21. Thus, the 24EE response to COLD further identifies the thrifty versus spendthrift phenotype, providing an additional setting to investigate the physiological mechanisms underlying the human metabolic phenotype and characterizing the individual susceptibility to weight change. © 2020 by the American Diabetes Association.RUNX3, a RUNX family transcription factor, regulates normal hematopoiesis and functions as a tumor suppressor in various tumors in humans and mice. However, emerging studies have documented increased expression of RUNX3 in hematopoietic stem/progenitor cells (HSPC) of a subset of patients with myelodysplastic syndrome (MDS) showing a worse outcome, suggesting an oncogenic function for RUNX3 in the pathogenesis of hematological malignancies. To elucidate the oncogenic function of RUNX3 in the pathogenesis of MDS in vivo, we generated a RUNX3-expressing, Tet2-deficient mouse model with the pan-cytopenia and dysplastic blood cells characteristic of MDS in patients. RUNX3-expressing cells markedly suppressed the expression levels of Runx1, a critical regulator of hemaotpoiesis in normal and malignant cells, as well as its target genes, which included crucial tumor suppressors such as Cebpa and Csf1r. RUNX3 bound these genes and remodeled their Runx1 binding regions in Tet2-deficient cells. Overexpression of RUNX3 inhibited the transcriptional function of Runx1 and compromised hematopoiesis to facilitate the development of MDS in the absence of Tet2, indicating that RUNX3 is an oncogene. Furthermore, overexpression of RUNX3 activated the transcription of Myc target genes and rendered cells sensitive to inhibition of Myc-Max heterodimerization. Collectively, these results reveal the mechanism by which RUNX3 overexpression exerts oncogenic effects on the cellular function of and transcriptional program in Tet2-deficient stem cells to drive the transformation of MDS. Copyright ©2020, American Association for Cancer Research.In incurable castration-resistant prostate cancer (CRPC), resistance to the novel androgen receptor (AR) antagonist enzalutamide (ENZ) is driven mainly by AR overexpression. Here we report that the expression of interferon regulatory factor 8 (IRF8) is increased in primary prostate cancer (PCa) but decreased in CRPC compared to normal prostate tissue. Decreased expression of IRF8 positively associated with CRPC progression and ENZ resistance. IRF8 interacted with AR and promoted its degradation via activation of the ubiquitin/proteasome systems. Epigenetic knockdown of IRF8 promoted AR-mediated PCa progression and ENZ resistance in vitro and in vivo. Furthermore, IFNα increased expression of IRF8 and improved the efficacy of ENZ in CRPC by targeting the IRF8-AR axis. We also provide preliminary evidence for the efficacy of IFNα with hormonotherapy in a clinical study. Collectively, this study identifies IRF8 both as a tumor suppressor in PCa pathogenesis and a potential alternative therapeutic option to overcome ENZ resistance. Copyright ©2020, American Association for Cancer Research.p27 binds and inhibits cyclin-CDK to arrest the cell cycle. p27 also regulates other processes including migration and development independent of its CDK inhibitory action. p27 is an atypical tumor suppressor deletion or mutational inactivation of the gene encoding p27, CDKN1B, is rare in human cancers. p27 is rarely fully lost in cancers because it can play both tumor suppressive and oncogenic roles. Until recently, the paradigm was that oncogenic deregulation results from either loss of growth restraint due to either excess p27 proteolysis or from an oncogenic gain of function through PI3K-mediated C-terminal p27 phosphorylation, which disrupts the cytoskeleton to increase cell motility and metastasis. In cancers, C-terminal phosphorylation alters p27 protein-protein interactions and shifts p27 from CDK inhibitor to oncogene. Accumulating data indicate p27 regulates transcription and acts as a transcriptional co-regulator of cJun. C-terminal p27 phosphorylation increases p27-cJun recruitment to and action on target genes to drive oncogenic pathways and repress differentiation programs. This review focuses on non-canonical, CDK-independent functions of p27 in migration, invasion, development, and gene expression, with emphasis on how transcriptional regulation by p27 illuminates its actions in cancer. A better understanding of how p27-associated transcriptional complexes are regulated might identify new therapeutic targets at the interface between differentiation and growth control. Copyright ©2020, American Association for Cancer Research.Metastasis is the major cause of mortality for cancer patients, and dysregulation of developmental signaling pathways can significantly contribute to the metastatic process. The SIX1/EYA transcriptional complex plays a critical role in the development of multiple organs and is typically downregulated after development is complete. In breast cancer, aberrant expression of SIX1 has been demonstrated to stimulate metastasis through activation of TGF-β signaling and subsequent induction of epithelial-mesenchymal transition (EMT). In addition, SIX1 can induce metastasis via non-cell autonomous means, including activation of GLI-signaling in neighboring tumor cells and activation of VEGF-C-induced lymphangiogenesis. Thus, targeting SIX1 would be expected to inhibit metastasis while conferring limited side effects. However, transcription factors are notoriously difficult to target, and thus novel approaches to inhibit their action must be taken. Here we identified a novel small molecule compound, NCGC00378430 (abbreviated as 8430), that reduces the SIX1/EYA2 interaction.