Phosphoglucomutase 1 inhibits hepatocellular carcinoma progression by regulating glucose trafficking.
Phosphoglucomutase 1 inhibits hepatocellular carcinoma progression by regulating glucose trafficking.
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磷酸葡萄糖变位酶 1 通过调节葡萄糖运输抑制肝细胞癌进展
DOI：
10.1371/journal.pbio.2006483
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发表时间：
2018-10
期刊：
影响因子：
9.8
通讯作者：
Yang W
中科院分区：
文献类型：
--
作者：
Jin GZ;Zhang Y;Cong WM;Wu X;Wang X;Wu S;Wang S;Zhou W;Yuan S;Gao H;Yu G;Yang W
糖原代谢在癌症中的改变才刚刚开始被理解。葡萄糖磷酸变位酶1（PGM 1）是糖原生成中第一个催化葡萄糖1-磷酸（G-1-P）和葡萄糖6-磷酸（G-6-P）可逆转化的酶，参与糖原的分解和合成。在这里，我们发现，PGM 1在肝细胞癌（HCC）中表达下调，这与HCC的恶性程度和预后不良有关。PGM 1表达减少阻碍了糖原生成途径，导致葡萄糖进入糖酵解的流量增加，从而促进肿瘤细胞增殖和HCC的发展。叉头盒蛋白J2（FOXJ 2）的缺失至少部分是由于HCC中基因组拷贝数低，释放细胞核酸结合蛋白（CNBP），一种核酸伴侣，结合并促进PGM 1启动子中的G-四链体形成，从而降低PGM 1表达。此外，联合分析PGM 1和FOXJ 2的表达可更好地预测HCC的发生和预后。本研究通过调节葡萄糖转运确立了PGM 1的肿瘤抑制作用，并揭示了PGM 1表达的一种新的调节机制。肝细胞癌（HCC）是成人中最常见的原发性肝癌类型。索拉非尼是唯一一种临床批准用于晚期HCC患者的全身药物。新靶点和生物标志物的鉴定将为晚期肝癌提供新的治疗策略和更好的预后预测。葡萄糖磷酸变位酶（Phosphoglucomutase，PGM）是一种进化上保守的酶，催化葡萄糖1-磷酸（glucose 1-phosphate，G-1-P）和葡萄糖6-磷酸（glucose 6-phosphate，G-6-P）的双向转化，是葡萄糖代谢中最重要的途径之一。在这项研究中，我们确定PGM 1作为一种代谢性肿瘤抑制因子。其表达将更多的葡萄糖分配给糖原生成，这减少了用于生物合成的糖酵解中间体，从而阻碍HCC进展。我们描述了肝癌中PGM 1下调的机制，发现叉头盒蛋白J2（FOXJ 2）缺失释放细胞核酸结合蛋白（CNBP）结合并修饰PGM 1启动子的DNA结构，从而抑制PGM 1的表达。人HCC肿瘤的免疫组化分析表明，FOXJ 2和PGM 1的低表达与人HCC的恶性程度和进展不良相关。这些结果还表明，残余PGM 1的激活可能会通过将糖酵解转变为糖原生成来损害肝癌的发展。
Glycogen metabolism commonly altered in cancer is just beginning to be understood. Phosphoglucomutase 1 (PGM1), the first enzyme in glycogenesis that catalyzes the reversible conversion between glucose 1-phosphate (G-1-P) and glucose 6-phosphate (G-6-P), participates in both the breakdown and synthesis of glycogen. Here, we show that PGM1 is down-regulated in hepatocellular carcinoma (HCC), which is associated with the malignancy and poor prognosis of HCC. Decreased PGM1 expression obstructed glycogenesis pathway, which leads to the increased flow of glucose into glycolysis, thereby promoting tumor cell proliferation and HCC development. The loss of forkhead box protein J2 (FOXJ2), at least partly due to low genomic copy number in HCC, releases cellular nucleic acid-binding protein (CNBP), a nucleic acid chaperon, to bind to and promote G-quadruplex formation in PGM1 promoter and therefore decreases PGM1 expression. In addition, integrated analyses of PGM1 and FOXJ2 expression provide a better prediction for the malignance and prognosis of HCC. This study establishes a tumor-suppressive role of PGM1 by regulating glucose trafficking and uncovers a novel regulatory mechanism of PGM1 expression. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults. Sorafenib is the only clinically approved systemic drug for patients with advanced HCC. Identification of novel targets and biomarkers will provide new therapeutic strategies for advanced HCC and better prognostic prediction. Phosphoglucomutase (PGM) is an evolutionarily conserved enzyme that regulates one of the most important pathways in glucose metabolis—catalyzing the bidirectional interconversion of glucose 1-phosphate (G-1-P) and glucose 6-phosphate (G-6-P). In this study, we identify PGM1 as a metabolic tumor suppressor. Its expression allocates more glucose to glycogenesis, which reduces the glycolytic intermediates for biosynthesis, thereby impairing HCC progression. We delineate the mechanism of PGM1 down-regulation in HCC, finding that forkhead box protein J2 (FOXJ2) loss releases cellular nucleic acid-binding protein (CNBP) to bind to and modify the DNA structure of PGM1 promoter, thereby inhibiting PGM1 expression. Immunohistochemical analyses of human HCC tumors indicate that low FOXJ2 and PGM1 expression correlates with the malignancy and poor progression of human HCC. These results also suggest that the activation of residual PGM1 may impair HCC development through switching glycolysis to glycogenesis.
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