Zhao Xiaoya, Fu Jianfei, Hu Bin, Chen Lin, Wang Jing, Fang Jinyong, Ge Chenyang, Lin Haiping, Pan Kailing, Fu Liang, Wang Lude, Du Jinlin, Xu Wenxia
Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China.
Department of Medical Oncology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Front Cell Dev Biol. 2021 May 12;9:639111. doi: 10.3389/fcell.2021.639111. eCollection 2021.
Metabolic reprogramming is a vital factor in the development of many types of cancer, including colon cancer. Serine metabolic reprogramming is a major feature of tumor metabolism. Yes-associated protein (YAP) participates in organ size control and tumorigenesis. However, the relationship between YAP and serine metabolism in colon cancer is unclear. In this study, RNA sequencing and metabolomics analyses indicated significant enrichment of the glycine, serine, and threonine metabolism pathways in serine starvation-resistant cells. Short-term serine deficiency inhibited YAP activation, whereas a prolonged response dephosphorylated YAP and promoted its activity. Mechanistically, USP7 increases YAP stability under increased serine conditions by regulating deubiquitination. Verteporfin (VP) effectively inhibited the proliferation of colon cancer cells and organoids and could even modulate serine metabolism by inhibiting USP7 expression. Clinically, YAP was significantly activated in colon tumor tissues and positively correlated with the expression of phosphoglycerate dehydrogenase (PHGDH) and USP7. Generally, our study uncovered the mechanism by which serine metabolism regulates YAP via USP7 and identified the crucial role of YAP in the regulation of cell proliferation and tumor growth; thus, VP may be a new treatment for colon cancer.
代谢重编程是包括结肠癌在内的多种癌症发展中的一个关键因素。丝氨酸代谢重编程是肿瘤代谢的一个主要特征。Yes相关蛋白（YAP）参与器官大小控制和肿瘤发生。然而，YAP与结肠癌中丝氨酸代谢之间的关系尚不清楚。在本研究中，RNA测序和代谢组学分析表明，在丝氨酸饥饿抗性细胞中，甘氨酸、丝氨酸和苏氨酸代谢途径显著富集。短期丝氨酸缺乏抑制YAP激活，而长期反应使YAP去磷酸化并促进其活性。从机制上讲，USP7在丝氨酸水平升高的条件下通过调节去泛素化增加YAP稳定性。维替泊芬（VP）有效抑制结肠癌细胞和类器官的增殖，甚至可以通过抑制USP7表达来调节丝氨酸代谢。临床上，YAP在结肠肿瘤组织中显著激活，且与磷酸甘油酸脱氢酶（PHGDH）和USP7的表达呈正相关。总体而言，我们的研究揭示了丝氨酸代谢通过USP7调节YAP的机制，并确定了YAP在调节细胞增殖和肿瘤生长中的关键作用；因此，VP可能是结肠癌的一种新的治疗方法。
