Jia Yu, Li Hui-Yan, Wang Jue, Wang Ying, Zhang Peng, Ma Ning, Mo Shi-Jing
Cancer Research Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030, Wuhan, Hubei, People's Republic of China.
General Surgical Laboratory, The First Affiliated Hospital, Sun Yat-Sen University, 510080, Guangzhou, Guangdong, People's Republic of China.
Oncogenesis. 2019 May 10;8(5):31. doi: 10.1038/s41389-019-0143-1.
Hypoxic microenvironment deregulates metabolic homeostasis in cancer cells albeit the underlying mechanisms involved in this process remain hitherto enigmatic. 14-3-3ζ/Yes-associated protein (YAP) axis plays a principal role in malignant transformation and tumor development. Here, we report that hypoxia disassembles 14-3-3ζ from YAP and thereby promotes YAP nuclear localization mediated by ERK2, which directly binds to the D-site of mitogen-activated protein kinase (MAPK) docking domain in 14-3-3ζ Leu98/100 and phosphorylates 14-3-3ζ at Ser37. When localizing in nucleus, YAP recruits at pyruvate kinase M2 (PKM2) gene promoter with hypoxia-inducible factor 1α (HIF-1α), for which PKM2 transcription is required. 14-3-3ζ Ser37 phosphorylation is instrumental for the hypoxia-induced glucose uptake, lactate production, and clonogenicity of pancreatic ductal adenocarcinoma (PDAC) cells, as well as tumorigenesis in mice. The 14-3-3ζ Ser37 phosphorylation positively correlates with p-ERK1/2 activity and HIF-1α expression in clinical samples from patients with PDAC and predicts unfavorable prognosis. Our findings underscore an appreciable linkage between YAP transcriptional activation and hypoxic glycolysis governed by ERK2-dependent 14-3-3ζ Ser37 phosphorylation for malignant progression of PDAC.
缺氧微环境会破坏癌细胞中的代谢稳态，尽管这一过程中涉及的潜在机制迄今仍不明确。14-3-3ζ/Yes相关蛋白（YAP）轴在恶性转化和肿瘤发展中起主要作用。在此，我们报告缺氧使14-3-3ζ与YAP分离，从而促进由ERK2介导的YAP核定位，ERK2直接结合14-3-3ζ亮氨酸98/100处有丝分裂原激活蛋白激酶（MAPK）对接结构域的D位点并在丝氨酸37处磷酸化14-3-3ζ。当定位于细胞核时，YAP与缺氧诱导因子1α（HIF-1α）一起募集到丙酮酸激酶M2（PKM2）基因启动子处，而PKM2转录是必需的。14-3-3ζ丝氨酸37磷酸化对缺氧诱导的胰腺导管腺癌（PDAC）细胞的葡萄糖摄取、乳酸产生和克隆形成能力以及小鼠肿瘤发生至关重要。在PDAC患者的临床样本中，14-3-3ζ丝氨酸37磷酸化与p-ERK1/2活性和HIF-1α表达呈正相关，并预示不良预后。我们的研究结果强调了YAP转录激活与由ERK2依赖性14-3-3ζ丝氨酸37磷酸化控制的缺氧糖酵解之间的明显联系，这对PDAC的恶性进展具有重要意义。
