Department of General Surgery, The Second Affiliated Hospital of Anhui Medical University, Hefei, China.
Department of Molecular Pathology, Hefei Da'an Medical Laboratory Co., Ltd, Hefei, China.
Clin Exp Pharmacol Physiol. 2023 Jul;50(7):561-572. doi: 10.1111/1440-1681.13773. Epub 2023 Apr 11.
Aerobic glycolysis is critical for the energy metabolism of cancer cells. This study focuses on the regulation of forkhead box A2 (FOXA2) on pyruvate kinase M2 (PKM2) and their effects on the glycolytic activity and malignant phenotype of thyroid carcinoma (THCA) cells. By analysing four Gene Expression Omnibus datasets and querying bioinformatics systems, we obtained FOXA2 as a poorly expressed transcription factor in THCA. Later, we validated decreased mRNA and protein levels of FOXA2 in THCA cells by quantitative polymerase chain reaction and western blot assays. FOXA2 upregulation in THCA cells suppressed the glucose uptake and lactate production, and it reduced the extracellular acidification rate, but increased the oxygen consumption rate of cells. Meanwhile, the FOXA2 overexpression blocked the proliferation and mobility, and the tumourigenic activity of cancer cells. The chromatin immunoprecipitation and luciferase assays showed that FOXA2 bound to PKM2 promoter and suppressed the transcription of PKM2, which was highly expressed in THCA cells. Further upregulation of PKM2 elevated the β-catenin, c-Myc and cyclin D1 levels and restored the glycolytic activity as well as the malignant properties of cancer cells. Collectively, this work reveals that FOXA2 suppresses aerobic glycolysis and progression of THCA by blocking PKM2 transcription and inactivating the Wnt/β-catenin pathway.
有氧糖酵解对癌细胞的能量代谢至关重要。本研究聚焦于叉头框蛋白 A2（FOXA2）对丙酮酸激酶 M2（PKM2）的调节及其对甲状腺癌（THCA）细胞糖酵解活性和恶性表型的影响。通过分析四个基因表达综合数据集并查询生物信息学系统，我们发现 FOXA2 在 THCA 中表达水平较低。随后，我们通过定量聚合酶链反应和 Western blot 实验验证了 THCA 细胞中 FOXA2 的 mRNA 和蛋白水平降低。FOXA2 在 THCA 细胞中的上调抑制了葡萄糖摄取和乳酸生成，降低了细胞外酸化率，但增加了细胞的耗氧量。同时，FOXA2 的过表达抑制了癌细胞的增殖和迁移以及致瘤活性。染色质免疫沉淀和荧光素酶实验表明，FOXA2 结合于 PKM2 启动子并抑制其转录，而 PKM2 在 THCA 细胞中高表达。进一步上调 PKM2 水平可提高β-连环蛋白、c-Myc 和 cyclin D1 水平，并恢复糖酵解活性以及癌细胞的恶性特性。综上所述，本研究揭示了 FOXA2 通过阻断 PKM2 转录和失活 Wnt/β-连环蛋白通路来抑制 THCA 的有氧糖酵解和进展。
