[Keywords: YAP; Lats; Mst; contact inhibition; NF2; Hippo] Supplemental material is available at http://www.genesdev.org.

Emerging evidence supports the pivotal roles of cancer-associated cachexia in breast cancer progression. However, the mediators and mechanisms that mediate cancer-induced cachexia remain unclear. Here, we show that breast cancer-derived exosomes alter adipocytes and muscle cells in terms of increased catabolism characterized by the release of metabolites. Likewise, tumour cells cocultivated with mature adipocytes or C2C12 exhibit an aggressive phenotype through inducing epithelial-mesenchymal transition. Mechanistically, we show that cancer cell-secreted miR-155 promotes beige/brown differentiation and remodel metabolism in resident adipocytes by downregulating the PPARγ expression, but does not significantly affect biological conversion in C2C12. In vitro the use of propranolol ameliorates tumour exosomes-associated cachectic wasting through upregulating the PPARγ expression. These results demonstrate that cancer-derived exosomes reprogram systemic energy metabolism and accelerate cancer-associated cachexia to facilitate tumour progression.Electronic supplementary materialThe online version of this article (10.1186/s12943-018-0899-5) contains supplementary material, which is available to authorized users.

Previous studies have shown that mitochondrial dysfunction plays an important role in high- glucose(HG)-induced podocyte injury and thus contributes to the progression of diabetic nephropathy(DN). The histone deacetylase Sirtuin6 (Sirt6) has been revealed to have an essential role in the regulation of mitochondrial function in skeletal muscle and cardiomyocytes. However, its specific role in mitochondrial homeostasis in podocytes is undetermined. Here, we aimeds to explore the physiological function of Sirt6 in podocyte mitochondria and apoptosis under HG conditions and explore the possible mechanism. Herein, we observed that Sirt6-WT-1 colocalization was suppressed in the glomeruli of patients with DN. In addition, diabetic mice exhibited reduced Sirt6 expression and AMP kinase (AMPK) dephosphorylation accompanied by mitochondrial morphological abnormalities. In vitro, podocytes exposed to HG presented with mitochondrial morphological alterations and podocyte apoptosis accompanied by Sirt6 and p-AMPK downregulation. In addition, HG promoted a decrease in mitochondrial number and an increase in mitochondrial superoxide production as well as a decreased mitochondrial membrane potential. ROS production was also increased in HG-treated podocytes. Conversely, all these mitochondrial defects induced by HG were significantly alleviated by Sirt6 plasmid transfection. Sirt6 overexpression simultaneously alleviated HG-induced podocyte apoptosis and oxidative stress, as well as increased AMPK phosphorylation. Increased levels of H3K9ac and H3K56ac induced by HG were attenuated in podocytes transfected with Sirt6 plasmids. Therefore, these results elucidated that Sirt6 protects mitochondria of podocytes and exerts anti-apoptotic effects via activating AMPK pathway. The present findings provide key insights into the pivotal role of mitochondria regulation by SIRT6 in its protective effects on podocytes.

Angiotensin II (Ang II) is a risk factor for the initiation and progression of chronic kidney disease (CKD), as elevated Ang II levels can lead to podocyte injury. However, there have been no studies on the role of Ang II in lipid metabolism or on podocyte injury caused by lipid dysfunction. Our study showed that Ang II induced lipid droplet (LD) accumulation and expression of the LD marker adipose differentiation-related protein (ADRP) in podocytes, and the extent of lipid deposition could be alleviated by losartan. Our study also demonstrated that Ang II increased the content of cholesterol in podocytes, which is an LD component, and this change was accompanied by decreased expression of the cholesterol efflux-related molecule ATP-binding cassette transporter-1 (ABCA1) and increased expression of the cholesterol uptake-related molecule LDL receptor (LDLR) and the cholesterol synthesis-related molecules sterol regulatory element-binding protein (SREBP1 and SREBP2) and 3-hydroxy-3-methylglutaryl CoA reductase (HMGCR). Pretreating podocytes with methyl-β-cyclodextrin (CD), which induces cholesterol efflux, decreased Ang II-mediated cholesterol accumulation and Ang II-induced podocyte apoptosis and maintained the podocyte cytoskeleton and spreading. These results suggested that Ang II induced podocyte cholesterol accumulation by regulating the expression of cholesterol metabolism-related molecules and that the subsequent cholesterol metabolism dysfunction resulted in podocyte injury.

No abstract