Lung adenocarcinoma (LUAD) is a deadly disease with a hallmark of aberrant metabolism. TEA domain 4 (TEAD4) is involved in the progression of several forms of cancer including LUAD. However, the role of TEAD4 in LUAD glucose metabolism is rarely reported as well as its potential mechanisms. Pyruvate kinase isozymes M2 (PKM2), the key regulatory enzymes in glycolysis, was predicted to be a target for TEAD4 by bioinformatics analysis. Thus, we aimed to explore whether TEAD4/PKM2 axis was related to LUAD glucose metabolism and malignant phenotype. The expression level of TEAD4 and PKM2 was measured by quantitative real-time PCR and Western blot. Luciferase reporter assay were employed to verify the effect of TEAD4 on PKM2 promoter as well as TEAD4/PKM2 axis on reporter activity of hypoxia inducible factor-1α (HIF-1α). Glycolysis was investigated according to glucose consumption, lactate production and the extracellular acidification rate. The present study indicated that TEAD4 and PKM2 were upregulated in LUAD and closely related to prognosis. Mechanistic investigations identified that TEAD4 played a key role as a transcription factor and promoted PKM2 transcription and expression, which further altered the reporter activity of HIF-1α and upregulated HIF-1α-targeted glycolytic genes glucose transporter-1 and hexokinase II. Functional assays revealed that TEAD4 and PKM2 affected glycolytic and 2-DG blocked the positive function of TEAD4 and PKM2 on glycolytic. Besides, TEAD4/PKM2 axis affects LUAD cell viability, apoptosis, migration, and invasion. Together, these data provided evidence that both TEAD4 and PKM2 were poor prognosticator. Targeting TEAD4/PKM2 axis might be an effective therapeutic strategy for LUAD.

中文翻译：

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转录因子 TEAD4 通过增强 PKM2 介导的糖酵解促进肺腺癌进展


肺腺癌（LUAD）是一种致命的疾病，其特点是代谢异常。 TEA 结构域 4 (TEAD4) 参与包括 LUAD 在内的多种癌症的进展。然而，TEAD4在LUAD葡萄糖代谢中的作用及其潜在机制却鲜有报道。通过生物信息学分析，丙酮酸激酶同工酶 M2 (PKM2) 是糖酵解中的关键调节酶，预计将成为 TEAD4 的靶标。因此，我们旨在探讨TEAD4/PKM2轴是否与LUAD葡萄糖代谢和恶性表型相关。通过实时定量PCR和Western blot检测TEAD4和PKM2的表达水平。采用荧光素酶报告基因测定来验证 TEAD4 对 PKM2 启动子以及 TEAD4/PKM2 轴对缺氧诱导因子 1α (HIF-1α) 报告基因活性的影响。根据葡萄糖消耗、乳酸产生和细胞外酸化率研究糖酵解。本研究表明TEAD4和PKM2在LUAD中表达上调且与预后密切相关。机制研究发现，TEAD4 作为转录因子发挥着关键作用，促进 PKM2 转录和表达，进一步改变 HIF-1α 的报告基因活性，并上调 HIF-1α 靶向的糖酵解基因葡萄糖转运蛋白-1 和己糖激酶 II。功能分析显示TEAD4和PKM2影响糖酵解，2-DG阻断TEAD4和PKM2对糖酵解的正功能。此外，TEAD4/PKM2 轴影响 LUAD 细胞活力、凋亡、迁移和侵袭。这些数据共同提供了证据，表明 TEAD4 和 PKM2 都是较差的预测因子。靶向 TEAD4/PKM2 轴可能是 LUAD 的有效治疗策略。