Recent studies on mutations in cancer genomes have distinguished driver mutations from passenger mutations, which occur as byproducts of cancer development. The cancer genome atlas (TCGA) project identified 299 genes and 24 pathways/biological processes that drive tumor progression (Cell 173: 371-385 e318, 2018). Of the 299 driver genes, 12 genes are involved in histones, histone methylation, and demethylation. Among these 12 genes, those encoding the histone demethylases JARID1C/KDM5C and UTX/KDM6A were identified as cancer driver genes. Furthermore, gain-of-function mutations in genes encoding metabolic enzymes, such as isocitrate dehydrogenases (IDH)1/2, drive tumor progression by producing an oncometabolite, D-2-hydroxyglutarate (D-2HG), which is a competitive inhibitor of α-ketoglutarate, O 2 -dependent dioxygenases such as Jumonji domain-containing histone demethylases, and DNA demethylases. Studies on oncometabolites suggest that histone demethylases mediate metabolic changes in chromatin structure. We have reviewed the most recent findings regarding cancer-specific metabolic reprogramming and the tumor-suppressive roles of JARID1C/KDM5C and UTX/KDM6A. We have also discussed mutations in other isoforms such as the JARID1A, 1B, 1D of KDM5 subfamilies and the JMJD3/KDM6B of KDM6 subfamilies, which play opposing roles in tumor progression as oncogenes or tumor suppressors depending on the cancer cell type.

Under low oxygen tension, cells increase the transcription of specific genes involved in angiogenesis, erythropoiesis, and glycolysis. Hypoxia-induced gene expression depends primarily on stabilization of the ␣ subunit of hypoxia-inducible factor-1 (HIF-1␣), which acts as a heterodimeric trans-activator with the nuclear protein known as the aryl hydrocarbon receptor nuclear translocator (Arnt). The resulting heterodimer (HIF-1␣/Arnt) interacts specifically with the hypoxia-responsive element (HRE), thereby increasing transcription of the genes under HRE control. Our results indicate that the 90-kDa heat-shock protein (Hsp90) inhibitor radicicol reduces the hypoxia-induced expression of both endogenous vascular endothelial growth factor (VEGF) and HRE-driven reporter plasmids. Radicicol treatment (0.5 g/ml) does not significantly change the stability of the HIF-1␣ protein and does not inhibit the nuclear localization of HIF-1␣. However, this dose of radicicol significantly reduces HRE binding by the HIF-1␣/Arnt heterodimer. Our results, the first to show that radicicol specifically inhibits the interaction between the HIF-1␣/Arnt heterodimer and HRE, suggest that Hsp90 modulates the conformation of the HIF-1␣/Arnt heterodimer, making it suitable for interaction with HRE. Furthermore, we demonstrate that radicicol reduces hypoxia-induced VEGF expression to decrease hypoxia-induced angiogenesis.Cells adapt to hypoxia by up-regulating the transcription of specific genes involved in angiogenesis, erythropoiesis, and glycolysis. Pathologically, tumor hypoxia contributes directly to enhanced glucose metabolism and angiogenesis, which are major features of malignant progression. The genes up-regulated during hypoxia include vascular endothelial growth factor (VEGF), erythropoietin, and several glycolytic enzymes. These diverse, targeted genes are induced by a common trans-activator, hypoxia-inducible factor 1 (HIF-1) (Iyer et al., 1998;Bruick and McKnight, 2001b;Semenza, 2002).HIF-1 was first identified as a heterodimeric trans-activator composed of two subunits, HIF-1␣ and -␤, both of which belong to the growing family of basic-helix-loop-helix-PAS (bHLH-PAS) proteins, including period (Per), Arnt, and single-minded (Sim). The bHLH-PAS proteins share common characteristics: first, a bHLH-PAS protein dimerizes with a specific partner protein through the HLH-PAS domain. Second, a partner such as the aryl hydrocarbon receptor (AhR) or HIF-1␣ is activated by specific stimuli (i.e., xenobiotics or low oxygen tension, respectively) before translocating to the nucleus, where it heterodimerizes with a partner protein. Alternatively, Arnt, another bHLH-PAS protein, is constitutively located in the nucleus and interacts with several

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Both hypoxia and insulin induce common target genes, including vascular endothelial growth factors and several glycolytic enzymes. However, these two signals eventually trigger quite different metabolic pathways. Hypoxia induces glycolysis, resulting in anaerobic ATP production, while insulin increases glycolysis for energy storage. Hypoxia-induced gene expression is mediated by the hypoxia-inducible factor-1 ( As oxygen levels decrease, cells generate ATP mainly from anaerobic glycolysis in the cytoplasm since the lack of oxygen diminishes the oxidative phosphorylation pathway in mitochondria. The hypoxic cells enhance glucose utilization by increasing transcription of glucose transporter proteins (Glut-1 and -3) 1 and several glycolytic enzymes. Other genes involved in systemic responses to prolonged hypoxic stress include vascular endothelial growth factor (VEGF), which induces blood vessel formation at hypoxic sites; erythropoietin, which elevates the production of red blood cells; and inducible nitricoxide synthase, which induces vasodilation (1). These diverse target genes are induced by a common transactivator, hypoxiainducible factor 1 (HIF-1). HIF-1 is composed of two subunits, HIF-1␣ and Arnt, both of which contain a basic-helix-loop-helix (bHLH) domain and Per, Arnt, AhR, Sim (PAS) domains. Recent studies demonstrated that hydroxylation of HIF-1␣ at the 564 proline residue is catalyzed by HIF-1␣ proline hydroxylase using molecular oxygen as the substrate. The tumor suppressor von Hippel-Lindau (VHL) protein specifically interacts with hydroxylated HIF-1␣ and mediates the assembly of a complex that activates a ubiquitin-dependent proteasome. Ubiquitinated HIF-1␣ is degraded by the proteasome. When cells lack oxygen, proline is not hydroxylated, and therefore HIF-1␣ protein is accumulated (2-5). Stabilized HIF-1␣ protein translocates into nuclei and makes a heterodimer with its partner Arnt. The HIF-1␣/Arnt heterodimer specifically contacts the hypoxia-responsive elements (HREs: -ANACGTGC-), recruits their coactivator p300/CBP, and increases transcription of their target genes. It is expected that the basic region of Arnt contacts CGTG sequences, whereas HIF-1␣ determines the half-site specificity of HRE (6).Besides hypoxia, the nutritional state and hormones of the cell also regulate transcription of many glycolytic enzymes required for maintaining metabolic homeostasis. Insulin plays a central role in regulating the metabolic pathways associated with energy storage and utilization. It triggers the conversion of glucose into glycogen and triglycerides and inhibits gluconeogenesis. Insulin has been known to modulate cellular metabolism by modifying the activity or changing the cellular location of preexisting enzymes. Recently the regulation of gene expression by insulin has been recognized as a major function of this hormone (7). Insulin increases the transcription of fatty-acid synthase and acetyl-CoA synthetase, both of which are involved in lipogenesis. Insulin also increases the transcription of Gl...

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Wnt5a, a prototypic non-canonical Wnt, is an inflammatory factor elevated in the sera of obese humans and mice. In the present study, fat-specific knockout of Wnt5a (Wnt5a-FKO) prevented HFD-induced increases in serum Wnt5a levels in male C57BL/6 J mice, which suggested adipocytes are primarily responsible for obesity-induced increases in Wnt5a levels. Mouse subcutaneous white adipose tissues (WATs) more sensitively responded to HFD, in terms of cell size increases and Wnt5a levels than epididymal WATs. Furthermore, adipocyte sizes were positively correlated with Wnt5a levels in vitro and in vivo. In hypertrophic adipocytes, enlarged lipid droplets increased cell stiffness and rearranged the f-actin stress fibers from the cytoplasm to the cortical region. The activities of YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif) increased in response to these mechanical changes in hypertrophic adipocytes, and inhibition or knock-down of YAP and TAZ reduced Wnt5a expression. ChIP (chromatin immunoprecipitation) analyses revealed that YAP was recruited by Wnt5a-1 gene promoter and increased Wnt5a expression. These results suggested that YAP responds to mechanical stress in hypertrophic adipocytes to induce the expression Wnt5a. When 8-week-old Wnt5a-FKO mice were fed an HFD for 20 weeks, the fat mass increased, especially in subcutaneous WATs, as compared with that observed in floxed mice, without significant changes in food intake or activity. Furthermore, Wnt5a-FKO mice showed impaired glucose tolerance regardless of diet type. Our findings show that hypertrophy/YAP/Wnt5a signaling constitutes a negative-feedback loop that retrains adipose tissue hypertrophy.

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