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Metabolic reprogramming in breast tumors is linked to increases in putative oncogenic metabolites that may contribute to malignant transformation. We previously showed that accumulation of the oncometabolite, 2-hydroxyglutarate (2HG), in breast tumors was associated with MYC signaling, but not with isocitrate dehydrogenase (IDH) mutations, suggesting a distinct mechanism for increased 2HG in breast cancer. Here, we determined that D-2HG is the predominant enantiomer in human breast tumors and show that the D-2HG-producing mitochondrial enzyme, alcohol dehydrogenase, iron-containing protein 1 (ADHFE1), is a breast cancer oncogene that decreases patient survival. We found that MYC upregulates ADHFE1 through changes in iron metabolism while coexpression of both ADHFE1 and MYC strongly enhanced orthotopic tumor growth in MCF7 cells. Moreover, ADHFE1 promoted metabolic reprogramming with increased formation of D-2HG and reactive oxygen, a reductive glutamine metabolism, and modifications of the epigenetic landscape, leading to cellular dedifferentiation, enhanced mesenchymal transition, and phenocopying alterations that occur with high D-2HG levels in cancer cells with IDH mutations. Together, our data support the hypothesis that ADHFE1 and MYC signaling contribute to D-2HG accumulation in breast tumors and show that D-2HG is an oncogenic metabolite and potential driver of disease progression., Introduction Breast tumors undergo metabolic reprogramming as part of malignant transformation (1, 2). This reprogramming leads to increased availability of putative oncogenic metabolites that are used for the synthesis of [...]

Intestinal farnesoid X receptor (FXR) signaling is involved in the development of obesity, fatty liver disease, and type 2 diabetes. However, the role of intestinal FXR in atherosclerosis and its potential as a target for clinical treatment have not been explored. The serum levels of fibroblast growth factor 19 (FGF19), which is encoded by an FXR target gene, were much higher in patients with hypercholesterolemia than in control subjects and were positively related to circulating ceramide levels, indicating a link between intestinal FXR, ceramide metabolism, and atherosclerosis. Among [ApoE.sup.-/-] mice fed a high-cholesterol diet (HCD), intestinal FXR deficiency (in [Fxr.sup.[DELTA]IE][ApoE.sup.-/-] mice) or direct FXR inhibition (via treatment with the FXR antagonist glycoursodeoxycholic acid [GUDCA]) decreased atherosclerosis and reduced the levels of circulating ceramides and cholesterol. Sphingomyelin phosphodiesterase 3 (SMPD3), which is involved in ceramide synthesis in the intestine, was identified as an FXR target gene. SMPD3 overexpression or C16:0 ceramide supplementation eliminated the improvements in atherosclerosis in [Fxr.sup.[DELTA]IE][ApoE.sup.-/-] mice. Administration of GUDCA or GW4869, an SMPD3 inhibitor, elicited therapeutic effects on established atherosclerosis in [ApoE.sup.-/-] mice by decreasing circulating ceramide levels. This study identified an intestinal FXR/SMPD3 axis that is a potential target for atherosclerosis therapy., Introduction Atherosclerosis is a chronic disease featuring hypercholesteremia and chronic inflammation (1). Farnesoid X receptor (FXR) is a ligand-activated nuclear receptor that regulates cholesterol and bile acid metabolism and has [...]

The dynamic interaction between nuclear proteins and chromatin leads to the functional plasticity necessary to mount adequate responses to regulatory signals. Here, we review the factors regulating the chromatin interactions of the high mobility group proteins (HMGs), an abundant and ubiquitous superfamily of chromatin-binding proteins in living cells. HMGs are highly mobile and interact with the chromatin fiber in a highly dynamic fashion, as part of a protein network. The major factors that affect the binding of HMGs to chromatin are operative at the level of the single nucleosome. These factors include structural features of the HMGs, competition with other chromatin-binding proteins for nucleosome binding sites, complex formation with protein partners, and post-translational modifications in the protein or in the chromatin-binding sites. The versatile modulation of the interaction between HMG proteins and chromatin plays a role in processes that establish the cellular phenotype. Key words: chromatin, HMG proteins, protein-DNA interactions. L'interaction dynamique des proteines nucleaires avec la chromatine fournit la plasticite fonctionnelle necessaire a l'etablissement d'une reponse appropriee aux signaux regulateurs. Nous passons ici en revue les facteurs qui regulent les interactions entre la chromatine et les HMG, des proteines abondantes et ubiquistes membres de la super-famille des proteines liant la chromatine, dans les cellules vivantes. Les HMG sont hautement mobiles et interagissent avec la fibre de chromatine de facon extremement dynamique au sein d'un reseau proteique. Les principaux facteurs qui affectent la liaison des HMG a la chromatine sont operationnels a l'echelle du nucleosome simple. Ces facteurs incluent des caracteristiques structurelles des HMG, la competition avec d'autres proteines liant la chromatine pour les sites de liaison au nucleosome, la formation de complexes avec des proteines partenaires et les modifications post-traductionnelles au niveau de la proteine ou des sites de liaison sur la chromatine. La modulation versatile des interactions des HMG avec la chromatine joue un role dans les processus qui etablissent le phenotype cellulaire. Mots-cles : chromatine, proteines HMG, interactions ADN-proteines. [Traduit par la Redaction], Introduction The dynamic and continuous interaction of nuclear regulatory factors and structural proteins with the chromatin fiber plays a key role in regulating the fidelity of gene expression and in [...]

Author(s): Tom Misteli (corresponding author) [1]; Akash Gunjan [2, 3]; Robert Hock [4]; Michael Bustin [5]; David T. Brown [2] The linker histone H1 is believed to be involved in [...]