Restoration of FBP1 suppressed Snail-induced epithelial to mesenchymal transition in hepatocellular carcinoma

Liu, Gao-Min; Li, Qiao; Zhang, Peng-Fei; Shen, Shunli; Xie, Wenlin; Chen, Bin; Wu, Jian; Hu, Wenjie; Huang, Xiaoyong; Peng, Baogang

doi:10.1038/s41419-018-1165-x

Cited by 39 publications

(37 citation statements)

References 31 publications

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“…Previous studies have shown that FBP1 epigenetic repression is common in several cancers, such as hepatocellular carcinoma (HCC), and colon and non-small cell lung, and breast cancer (Bigl et al, 2008;Chen et al, 2011;Liu et al, 2018). Specifically, in breast cancer cells, histone methyltransferase G9a and DNA methyltransferase DNMT1 are recruited to the FBP1 promoter by Snail, a critical factor in epithelial-to-mesenchymal transitions (EMTs), resulting in increased H3K9me2 and DNA methylation (Dong et al, 2013).…”

Section: Future Directionsmentioning

confidence: 99%

Fructose-1,6-Bisphosphatase 2 Inhibits Sarcoma Progression by Restraining Mitochondrial Biogenesis

Huangyang

Lee

et al. 2020

Cell Metabolism

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Sarcomas are uncommon but diverse mesenchymal malignancies arising from connective tissues, such as muscle, fat and cartilage. Despite rapid advances in molecular understanding of individual subtypes and pathway-specific therapies, the remarkable cellular and genetic heterogeneity of soft tissue sarcomas (STS) limits clinical benefit of targeted treatments. A variety of metabolism-associated oncogenic signaling pathways have been identified in sarcomas. Both these internal and external alterations converge to change cell metabolism, rendering sarcoma cells more susceptible to perturbations within metabolic networks. However, how abnormal metabolism influences sarcoma growth remains understudied. I show that expression of the gluconeogenic isozyme fructose-1,6-bisphosphatase 2 (FBP2) is silenced in a broad spectrum of STS subtypes, revealing an apparent common metabolic feature shared by diverse STS. Enforced FBP2 re-expression inhibits STS cell and tumor growth through two distinct mechanisms. First, cytosolic FBP2 antagonizes elevated glycolysis associated with the "Warburg effect", thereby inhibiting sarcoma cell proliferation. Second, nuclear-localized FBP2 restrains mitochondrial biogenesis and respiration in a catalytic activity-independent manner by inhibiting the expression of nuclear respiratory factor (NRF1) and mitochondrial transcription factor A (TFAM). Specifically, nuclear FBP2 colocalizes with the c-Myc transcription factor at the TFAM locus and represses c-Myc-dependent TFAM expression. This unique dual function of FBP2 provides a rationale for its selective suppression in STS, identifying a potential metabolic vulnerability and possible future therapeutic target.

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Section: Future Directionsmentioning

confidence: 99%

Fructose-1,6-Bisphosphatase 2 Inhibits Sarcoma Progression by Restraining Mitochondrial Biogenesis

Huangyang

Lee

et al. 2020

Cell Metabolism

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“…Notably, HCC patients with high Snail but low FBP1 expression were identified with the worst prognosis. Conversely, patients with low Snail but high FBP1 expression were identified with the best prognosis (67).…”

Section: Discussionmentioning

confidence: 95%

LOXL2 upregulates hypoxia‑inducible factor‑1α signaling through Snail‑FBP1 axis in hepatocellular carcinoma cells

Fan

Zheng

et al. 2020

Oncol Rep

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Lysyl oxidase-like 2 (LOXL2), a member of the lysyl oxidase gene family, is involved in the progression of hepatocellular carcinoma progression and metastasis. Increased expression of LOXL2 has been identified in several types of cancer, including hepatocellular carcinoma. Recently, LOXL2 has been reported to promote epithelial-mesenchymal transition by reducing E-cadherin expression via the upregulation of Snail expression. The present study provided evidence demonstrating that LOXL2 inhibited the expression of fructose-1, 6-biphosphatase (FBP1) and enhanced the glycolysis of Huh7 and Hep3B hepatocellular carcinoma cell lines in a Snail-dependent manner. Overexpression of the point-mutated form of LOXL2 [LOXL2(Y689F)], which lacks enzymatic activity, does not affect the expression of Snail1 or FBP1. Notably, targeting extracellular LOXL2 of Huh7 cells with a therapeutic antibody was unable to abolish its regulation on the expression of Snail and FBP1. Knockdown of LOXL2 also interrupted the angiogenesis of Huh7 and Hep3B cells, and this effect could be rescued by the overexpression of Snail. Furthermore, upregulation of hypoxia-inducible factor 1α (HIF-1α) and vascular endothelial growth factor (VEGF) expression was observed in Huh7 and Hep3B cells expressing wild-type LOXL2. Notably, the selective LOXL2 inhibitor LOXL2-IN-1 could upregulate the expression of FBP1 and inhibit the expression of Snail, HIF-1α and VEGF in HCC cells, but not in FBP1-knockdown cells. The results of the present study indicated that the intracellular activity of LOXL2 upregulated HIF-1α/VEGF signaling pathways via the Snail-FBP1 axis, and this phenomenon could be inhibited by LOXL2 inhibition. Collectively, these findings further support that LOXL2 exhibits an important role in the progression of hepatocellular carcinoma and implicates LOXL2 as a potential therapeutic agent for the treatment of this disease.

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“…FBP1 is a gluconeogenic enzyme that is upregulated in response to fructose exposure [33]. Clinical research has shown that low FBP1 expression is associated with poorer survival and more aggressive HCC growth [119][120][121][122][123][124]. Low FBP1 expression enhances glycolysis in HCC [122,124], while increasing FBP1 reduced GLUT1 expression, glucose uptake, lactate production, and cell growth [120,121,123].…”

Section: Genetic Changes Associated With Hcc May Reduce Fructose Metamentioning

confidence: 99%

A Sweet Connection? Fructose’s Role in Hepatocellular Carcinoma

et al. 2020

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Hepatocellular carcinoma is one of few cancer types that continues to grow in incidence and mortality worldwide. With the alarming increase in diabetes and obesity rates, the higher rates of hepatocellular carcinoma are a result of underlying non-alcoholic fatty liver disease. Many have attributed disease progression to an excess consumption of fructose sugar. Fructose has known toxic effects on the liver, including increased fatty acid production, increased oxidative stress, and insulin resistance. These effects have been linked to non-alcoholic fatty liver (NAFLD) disease and a progression to non-alcoholic steatohepatitis (NASH). While the literature suggests fructose may enhance liver cancer progression, the precise mechanisms in which fructose induces tumor formation remains largely unclear. In this review, we summarize the current understanding of fructose metabolism in liver disease and liver tumor development. Furthermore, we consider the latest knowledge of cancer cell metabolism and speculate on additional mechanisms of fructose metabolism in hepatocellular carcinoma.

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Restoration of FBP1 suppressed Snail-induced epithelial to mesenchymal transition in hepatocellular carcinoma

Cited by 39 publications

References 31 publications

Fructose-1,6-Bisphosphatase 2 Inhibits Sarcoma Progression by Restraining Mitochondrial Biogenesis

Fructose-1,6-Bisphosphatase 2 Inhibits Sarcoma Progression by Restraining Mitochondrial Biogenesis

LOXL2 upregulates hypoxia‑inducible factor‑1α signaling through Snail‑FBP1 axis in hepatocellular carcinoma cells

A Sweet Connection? Fructose’s Role in Hepatocellular Carcinoma

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