FOXM1 promotes the warburg effect and pancreatic cancer progression via transactivation of LDHA expression.
FOXM1 promotes the warburg effect and pancreatic cancer progression via transactivation of LDHA expression.
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FOXM1 通过 LDHA 表达的反式激活促进瓦尔堡效应和胰腺癌进展。
DOI：
10.1158/1078-0432.ccr-13-2407
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发表时间：
2014-05-15
期刊：
影响因子：
--
通讯作者：
Xie K
中科院分区：
文献类型：
--
作者：
Cui J;Shi M;Xie D;Wei D;Jia Z;Zheng S;Gao Y;Huang S;Xie K
转录因子叉头盒M1 （FOXM1）在癌症的发生和发展中起着关键作用。然而，FOXM1在肿瘤代谢中的调节作用和潜在机制尚不清楚。在本研究中，我们表征了FOXM1对有氧糖酵解的调节及其对胰腺癌代谢的影响。通过胰腺癌动物模型研究FOXM1表达改变对糖酵解酶表达和肿瘤发生进展的影响。此外，利用体外分子生物学分析了胰腺癌糖酵解改变的潜在机制。通过胰腺肿瘤和正常胰腺组织标本，确定FOXM1信号失调引起的异常代谢的临床相关性。我们发现FOXM1没有显著改变大多数糖酵解酶的表达，除了磷酸甘油酸激酶1和乳酸脱氢酶A （LDHA）。FOXM1和LDHA在胰腺肿瘤和癌细胞系中同时过表达。FOXM1表达的增加在mRNA和蛋白水平上上调了LDHA的表达，提高了LDH活性、乳酸生成和葡萄糖利用，而FOXM1表达的减少则相反。进一步的研究表明FOXM1直接结合到LDHA启动子区域，并在转录水平上调控LDHA基因的表达。此外，FOXM1-LDHA信号的升高促进了胰腺癌细胞的生长和转移。FOXM1的表达和激活失调通过转录调控LDHA表达在胰腺癌患者的有氧糖酵解和肿瘤发生中发挥重要作用。
The transcription factor Forkhead box M1 (FOXM1) plays critical roles in cancer development and progression. However, the regulatory role and underlying mechanisms of FOXM1 in cancer metabolism are unknown. In this study, we characterized the regulation of aerobic glycolysis by FOXM1 and its impact on pancreatic cancer metabolism. The effect of altered expression of FOXM1 on expression of glycolytic enzymes and tumor development and progression was examined using animal models of pancreatic cancer. Also, the underlying mechanisms of altered pancreatic cancer glycolysis were analyzed using in vitro molecular biology. The clinical relevance of aberrant metabolism caused by dysregulated FOXM1 signaling was determined using pancreatic tumor and normal pancreatic tissue specimens. We found that FOXM1 did not markedly change the expression of most glycolytic enzymes except for phosphoglycerate kinase 1 and lactate dehydrogenase A (LDHA). FOXM1 and LDHA were overexpressed concomitantly in pancreatic tumors and cancer cell lines. Increased expression of FOXM1 upregulated the expression of LDHA at both the mRNA and protein level and elevated LDH activity, lactate production, and glucose utilization, whereas reduced expression of FOXM1 did the opposite. Further studies demonstrated that FOXM1 bound directly to the LDHA promoter region and regulated the expression of the LDHA gene at the transcriptional level. Also, elevated FOXM1-LDHA signaling increased the pancreatic cancer cell growth and metastasis. Dysregulated expression and activation of FOXM1 play important roles in aerobic glycolysis and tumorigenesis in pancreatic cancer patients via transcriptional regulation of LDHA expression.