Kidney cancer: FBP1 depletion feeds ccRCC.
Kidney cancer: FBP1 depletion feeds ccRCC.
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DOI：
10.1038/nrurol.2014.200
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发表时间：
2014-09-01
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影响因子：
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通讯作者：
Phillips, Robert
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作者：
Phillips, Robert
发表在《自然》杂志上的新研究表明，葡萄糖合成中的限速酶-果糖-1，6-二磷酸酶1（FBP 1）-在透明细胞肾细胞癌（ccRCC）中普遍耗尽，通过抑制细胞生成和增强低氧诱导因子（HIF）对糖酵解基因的反式激活来促进癌症进展。糖酵解的激活为癌细胞提供了更高的能量需求。在> 90%的ccRCC肿瘤中，von Hippel-Lindau（VHL）突变导致HIF的常氧稳定，通过激活糖酵解基因刺激糖酵解。然而，小鼠中的VHL突变不足以诱导ccRCC，这表明还涉及其他机制。研究人员现在已经使用了各种技术来进一步表征ccRCC特异性代谢改变，确定其他致癌驱动因素。基因集分析发现，与正常肾组织相比，ccRCC肿瘤中碳水化合物储存组（包括控制肾血管生成的三个基因）的表达显著不足。在这些基因中，发现FBP 1（或FBP 1蛋白）在> 600个ccRCC肿瘤中下调。FBP 1抑制程度与肿瘤分期和患者预后显著相关。ccRCC细胞中的FBP 1抑制不依赖于HIF活化。接下来，在ccRCC细胞中FBP 1的异位表达显示出抑制生长-缺氧增强的效果。在VHL缺陷的ccRCC细胞系中，FBP 1表达减少了糖酵解，但在重新引入野生型VHL时恢复，这阻止了常氧HIF表达。FBP 1和HIF-1α共定位于HIF靶基因的缺氧反应元件，并降低VHL缺陷细胞中的基因表达，表明FBP 1直接抑制HIF介导的反式激活。这种抑制作用不依赖于FBP 1的C-末端致炎催化结构域，而是依赖于N-末端调节结构域。FBP 1的双重肿瘤抑制功能由负责肿瘤发生和抑制HIF活性的单独蛋白结构域介导，可以解释ccRCC肿瘤中FBP 1表达的普遍丧失。因此，FBP 1可能是未来治疗ccRCC的新靶点。
New research published in Nature suggests that the rate-limiting enzyme in glucose synthesis—fructose-1, 6-bisphosphatase 1 (FBP1)—is universally depleted in clear cell renal cell carcinoma (ccRCC), facilitating cancer progression by both suppressing gluconeogenesis and enhancing transactivation of glycolytic genes by hypoxia-inducible factors (HIFs). Activation of glycolysis feeds the elevated energy demands of cancer cells. In> 90% of ccRCC tumours, von Hippel–Lindau (VHL) mutations lead to normoxic stabilization of HIFs, stimulating glycolysis by activation of glycolytic genes. However, VHL mutation in mice is not sufficient to induce ccRCC, suggesting other mechanisms are involved. Researchers have now used a variety of techniques to further characterize ccRCC-specific metabolic alterations, identifying additional oncogenic drivers. Gene set analysis identified significant underexpression of the carbohydrate storage group, including three genes controlling renal gluconeogenesis, in ccRCC tumours compared with normal kidney tissue. Of these genes, FBP1 (or FBP1 protein) was found to be downregulated in> 600 ccRCC tumours. The extent of FBP1 suppression was significantly correlated with tumour stage and patient prognosis. FBP1 inhibition in ccRCC cells did not depend on HIF activation. Next, ectopic expression of FBP1 in ccRCC cells was shown to inhibit growth—an effect that was enhanced by hypoxia. Glycolysis was reduced by FBP1 expression in a VHL-deficient ccRCC cell line, but restored on reintroduction of wild-type VHL, which prevented normoxic HIF expression. FBP1 and HIF-1α co-localized at hypoxia response elements of HIF target genes and reduced gene expression in VHL-deficient cells, suggesting that FBP1 directly inhibits HIF-mediated transactivation. This inhibition was not dependent on the C-terminal gluconeogenic catalytic domain of FBP1, but on the N-terminal regulatory domain. The dual tumour-suppressive functions of FBP1, mediated by separate protein domains responsible for gluconeogenesis and for inhibition of HIF activity, could explain the universal loss of FBP1 expression in ccRCC tumours. FBP1 could, therefore, represent a novel target for future therapeutic interventions in ccRCC.