The metabolic gene HAO2 is downregulated in hepatocellular carcinoma and predicts metastasis and poor survival

Mattu, Sandra; Fornari, Francesca; Quagliata, Luca; Perra, Andrea; Angioni, Maria Maddalena; Petrelli, Annalisa; Menegon, Silvia; Morandi, Andrea; Chiarugi, Paola; Ledda-Columbano, Giovanna M.; Gramantieri, Laura; Terracciano, Luigi; Giordano, Silvia; Columbano, Amedeo

doi:10.1016/j.jhep.2015.11.029

Cited by 36 publications

(26 citation statements)

References 18 publications

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“…The answer may relate to our observation that the set of female-biased genes up-regulated in Ezh1/Ezh2-deficient male liver includes genes that confer protection from HCC in wild-type female liver. One example is Hao2, which is down-regulated in HCC, and its expression inversely correlates with metastasis and survival [70]. Hao2 is strongly induced in E1/E2-KO male liver, but to only ~60% the level of control (wild-type) female liver, and this increase in expression may not be not sufficient to counteract the severe liver injury generated by loss of Ezh1/Ezh2.…”

Section: Discussionmentioning

confidence: 99%

Sex-biased genetic programs in liver metabolism and liver fibrosis are controlled by EZH1 and EZH2

Lau-Corona

Bae

Hennighausen

et al. 2019

Preprint

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31Background: Sex differences in the incidence and progression of many liver diseases, including liver 32 fibrosis and hepatocellular carcinoma, are associated with sex-biased expression of hundreds of 33 genes in the liver. This sexual dimorphism is largely determined by the sex-specific pattern of pituitary 34 growth hormone secretion, which controls a transcriptional regulatory network operative in the context 35 of sex-biased chromatin states. Histone H3K27-trimethylation yields a major sex-biased repressive 36 chromatin mark that is specifically deposited by polycomb repressive complex-2, via its homologous 37 catalytic subunits Ezh1 and Ezh2, at many strongly female-biased genes in male mouse liver, but not 38 at male-biased genes in female liver. Results: We used Ezh1-knockout mice with a hepatocyte-39 specific knockout of Ezh2 to elucidate the sex bias of liver H3K27-trimethylation and its functional role 40 in regulating sex-differences in the liver. Combined hepatic Ezh1/Ezh2 deficiency led to a significant 41 loss of sex-biased gene expression, particularly in male liver, where many female-biased genes 42 increased in expression while male-biased genes showed decreased expression. The associated loss 43 of H3K27me3 marks, and increases in the active enhancer marks H3K27ac and H3K4me1, were also 44 more pronounced in male liver. Many genes linked to liver fibrosis and hepatocellular carcinoma were 45 induced in Ezh1/Ezh2-deficient livers, which may contribute to the increased sensitivity of these mice 46 to hepatotoxin-induced liver pathology. Conclusions: Ezh1/Ezh2-catalyzed H3K27-trimethyation is 47 thus essential for the sex-dependent epigenetic regulation of liver chromatin states controlling 48 phenotypic sex differences in liver metabolism and liver fibrosis, and may be a critical determinant of 49 the sex-bias in liver disease susceptibility. Background 52Liver disease shows marked sex differences. Hepatocellular carcinoma incidence and mortality is 53 three times higher in men than in women [1, 2], and male mice are more susceptible to chemical-54 induced hepatic carcinogenesis [3]. Males are also more susceptible to non-alcoholic fatty liver 55 disease, non-alcoholic steatohepatitis and liver fibrosis than females [4][5][6][7][8]. Underlying these sex-biased Lau-Corona et alPage 5 3/13/19 liver. Hepatic Ezh1/Ezh2 deficiency is also shown to down regulate many male-biased genes, 106presumed as a secondary response to the disruption of female-biased gene expression. Finally, we 107show that many genes associated with liver fibrosis and liver carcinogenesis are differentially 108 responsive to the loss of Ezh1/Ezh2 in male compared to female liver, which may contribute to the 109 observed sex-differences in the incidence and progression of liver cancer. 110 111 Methods 112 Animal tissues. Livers from 7-week-old male and female Ezh1-knockout mice with a hepatocyte-113 specific knockout of Ezh2 (E1/E2-KO mice, also designated Double-knockout (DKO) in the figures 114 and tables) and their age and sex...

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Section: Discussionmentioning

confidence: 99%

Sex-biased genetic programs in liver metabolism and liver fibrosis are controlled by EZH1 and EZH2

Lau-Corona

Bae

Hennighausen

et al. 2019

Preprint

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“…Several abnormal lipid metabolism factors are partially remedied by troxerutin treatment. For example, the synthesis of long chain fatty acids and the inhibition of fatty acid oxidation are the main mechanism of renal lipotoxicity associated with Acaca, Fasn, Hao2, and Acaa1b (65,66). Cyp4a10 can respond to increased catalase, intensifying aberrant lipid metabolism (67,68).…”

Section: Discussionmentioning

confidence: 99%

Precision toxicology shows that troxerutin alleviates ochratoxin A–induced renal lipotoxicity

Yang

Huang

et al. 2018

FASEB j.

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Lipotoxicity is the most common cause of severe kidney disease, with few treatment options available today. Precision toxicology can improve detection of subtle intracellular changes in response to exogenous substrates; thus, it facilitates in‐depth research on bioactive molecules that may interfere with the onset of certain diseases. In the current study, troxerutin significantly relieved nephrotoxicity, increased endurance, and improved systemic energy metabolism and renal inflammation in OTA‐induced nephrotic mice. Lipidomics showed that troxerutin effectively reduced the levels of triglycerides, phosphatidylcholines, and phosphatidylethanolamines in nephropathy. The mechanism was partly attributable to troxerutin in alleviating the aberrantly up‐regulated expression of sphingomyelinase, the cystic fibrosis transmembrane conductance regulator, and chloride channel 2. Renal tubular epithelial cells, the main site of toxin‐induced accumulation of lipids in the kidney, were subjected to transcriptomic profiling, which uncovered several metabolic factors relevant to aberrant lipid and lipoprotein metabolism. Our work provides new insights into the molecular features of toxin‐induced lipotoxicity in renal tubular epithelial cells in vivo and demonstrates the function of troxerutin in alleviating OTA‐induced nephrosis and associated systemic energy metabolism disorders.—Yang, X., Xu, W., Huang, K., Zhang, B., Wang, H., Zhang, X., Gong, L., Luo, Y., He, X. Precision toxicology shows that troxerutin alleviates ochratoxin A‐induced renal lipotoxicity. FASEB J. 33, 2212–2227 (2019). http://www.fasebj.org

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“…Thus, it is likely that the enhanced expression of this gene is specific for cells addressed to cancer progression and that the primary role of PPP induction is to maintain the redox equilibrium in preneoplastic cells, whereas pentoses can also be generated by the non-oxidative phase of PPP in a G6PD-independent manner [6]. Accordingly, we recently found that intracellular ROS levels are increased in tumorigenic cells compared to the non-tumorigenic counterpart [37]. In this context, it should be noted that the activation of NRF2/KEAP1 transcriptional pathway may play a critical role in G6PD increase.…”

Section: Discussionmentioning

confidence: 99%

Metabolic reprogramming identifies the most aggressive lesions at early phases of hepatic carcinogenesis

et al. 2016

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Metabolic changes are associated with cancer, but whether they are just bystander effects of deregulated oncogenic signaling pathways or characterize early phases of tumorigenesis remains unclear. Here we show in a rat model of hepatocarcinogenesis that early preneoplastic foci and nodules that progress towards hepatocellular carcinoma (HCC) are characterized both by inhibition of oxidative phosphorylation (OXPHOS) and by enhanced glucose utilization to fuel the pentose phosphate pathway (PPP). These changes respectively require increased expression of the mitochondrial chaperone TRAP1 and of the transcription factor NRF2 that induces the expression of the rate-limiting PPP enzyme glucose-6-phosphate dehydrogenase (G6PD), following miR-1 inhibition. Such metabolic rewiring exclusively identifies a subset of aggressive cytokeratin-19 positive preneoplastic hepatocytes and not slowly growing lesions. No such metabolic changes were observed during non-neoplastic liver regeneration occurring after two/third partial hepatectomy. TRAP1 silencing inhibited the colony forming ability of HCC cells while NRF2 silencing decreased G6PD expression and concomitantly increased miR-1; conversely, transfection with miR-1 mimic abolished G6PD expression. Finally, in human HCC patients increased G6PD expression levels correlates with grading, metastasis and poor prognosis. Our results demonstrate that the metabolic deregulation orchestrated by TRAP1 and NRF2 is an early event restricted to the more aggressive preneoplastic lesions.

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The metabolic gene HAO2 is downregulated in hepatocellular carcinoma and predicts metastasis and poor survival

Cited by 36 publications

References 18 publications

Sex-biased genetic programs in liver metabolism and liver fibrosis are controlled by EZH1 and EZH2

Sex-biased genetic programs in liver metabolism and liver fibrosis are controlled by EZH1 and EZH2

Precision toxicology shows that troxerutin alleviates ochratoxin A–induced renal lipotoxicity

Metabolic reprogramming identifies the most aggressive lesions at early phases of hepatic carcinogenesis

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