Department of Radiation Oncology, The First Affiliated Hospital of Guangxi Medical University, Nanning, China.
J Cell Mol Med. 2022 Jul;26(13):3783-3796. doi: 10.1111/jcmm.17413. Epub 2022 Jun 3.
The transcription factor forkhead box M1 (FOXM1) is a well-known proto-oncogene that plays a significant role in the pathogenesis of various human cancers. However, the regulatory role and underlying mechanisms of FOXM1 in nasopharyngeal carcinoma (NPC) metabolism remain unclear. We demonstrated that FOXM1 could positively regulate glycolysis in NPC cells. Functional studies have shown that pyruvate dehydrogenase kinase 1 (PDK1) is involved in FOXM1-regulated lactate production, ATP generation and glycolysis. FOXM1 binds directly to the PDK1 promoter region and increases the expression of PDK1 at the transcriptional level, leading to the phosphorylation of pyruvate dehydrogenase (PDH) at serine 293, inhibiting its activity. Knocking down FOXM1 using specific short hairpin RNAs (shRNAs) can significantly decrease glycolysis and the expression of PDK1 in NPC cells. Furthermore, microenvironmental factors can increase the expression of FOXM1 by regulating hypoxia-inducible factor 1α (HIF-1α) expression. Clinical data and in vivo studies confirmed the positive roles of FOXM1/PDK1 in NPC proliferation and progression. In conclusion, our findings revealed that FOXM1 regulates glycolysis and proliferation of NPC through PDK1-mediated PDH phosphorylation. Therefore, targeting the FOXM1-PDK1 axis may be a potential therapeutic strategy for NPC.
转录因子叉头框 M1（FOXM1）是一种众所周知的原癌基因，在多种人类癌症的发病机制中发挥重要作用。然而，FOXM1 在鼻咽癌（NPC）代谢中的调节作用和潜在机制尚不清楚。我们证明 FOXM1 可以正向调节 NPC 细胞中的糖酵解。功能研究表明，丙酮酸脱氢酶激酶 1（PDK1）参与了 FOXM1 调节的乳酸生成、ATP 生成和糖酵解。FOXM1 直接结合 PDK1 启动子区域，并在转录水平上增加 PDK1 的表达，导致丙酮酸脱氢酶（PDH）在丝氨酸 293 处磷酸化，抑制其活性。使用特异性短发夹 RNA（shRNA）敲低 FOXM1 可显著降低 NPC 细胞中的糖酵解和 PDK1 的表达。此外，微环境因素可以通过调节缺氧诱导因子 1α（HIF-1α）表达来增加 FOXM1 的表达。临床数据和体内研究证实了 FOXM1/PDK1 在 NPC 增殖和进展中的积极作用。总之，我们的研究结果表明，FOXM1 通过 PDK1 介导的 PDH 磷酸化调节 NPC 的糖酵解和增殖。因此，靶向 FOXM1-PDK1 轴可能是 NPC 的一种潜在治疗策略。
