Xue Xiangfei, Tian Xiaoting, Zhang Congcong, Miao Yayou, Wang Yikun, Peng Yingxiu, Qiu Shiyu, Wang Hong, Cui Jiangtao, Cao Leiqun, Sun Fenyong, Qiao Yongxia, Zhang Xiao
Department of Clinical Laboratory Medicine, Shanghai Tenth People's Hospital of Tongji University, Shanghai, 200072, China.
Shanghai Institute of Thoracic Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, Shanghai, 200030, China.
Cell Death Discov. 2022 Feb 11;8(1):59. doi: 10.1038/s41420-022-00842-8.
Yes-associated protein (YAP) activation is crucial for tumor formation and development, and its stability is regulated by ubiquitination. ISGylation is a type of ubiquitination like post-translational modification, whereas whether YAP is ISGylated and how ISGylation influences YAP ubiquitination-related function remains uncovered. In addition, YAP can activate glucose metabolism by activating the hexosamine biosynthesis pathway (HBP) and glycolysis, and generate a large number of intermediates to promote tumor proliferation. However, whether YAP stimulates the pentose phosphate pathway (PPP), another tumor-promoting glucose metabolism pathway, and the relationship between this stimulation and ISGylation needs further investigation. Here, we found that YAP was ISGylated and this ISGylation inhibited YAP ubiquitination, proteasome degradation, interaction with-beta-transducin repeat containing E3 ubiquitin-protein ligase (βTrCP) to promote YAP stability. However, ISGylation-induced pro-YAP effects were abolished by YAP K497R (K, lysine; R, arginine) mutation, suggesting K497 could be the major YAP ISGylation site. In addition, YAP ISGylation promoted cell viability, cell-derived xenograft (CDX) and patient-derived xenograft (PDX) tumor formation. YAP ISGylation also increased downstream genes transcription, including one of the key enzymes of PPP, 6-phosphogluconolactonase (6PGL). Mechanistically, YAP promoted 6PGL transcription by simultaneously recruiting SMAD family member 2 (SMAD2) and TEA domain transcription factor 4 (TEAD4) binding to the 6PGL promoter to activate PPP. In clinical lung adenocarcinoma (LUAD) specimens, we found that YAP ISGylation degree was positively associated with 6PGL mRNA level, especially in high glucose LUAD tissues compared to low glucose LUAD tissues. Collectively, this study suggested that YAP ISGylation is critical for maintaining its stability and further activation of PPP. Targeting ISGylated YAP might be a new choice for hyperglycemia cancer treatment.
Yes相关蛋白（YAP）的激活对肿瘤的形成和发展至关重要，其稳定性受泛素化调节。ISGylation是一种类似泛素化的翻译后修饰，然而YAP是否发生ISGylation以及ISGylation如何影响YAP泛素化相关功能仍不清楚。此外，YAP可通过激活己糖胺生物合成途径（HBP）和糖酵解来激活葡萄糖代谢，并产生大量中间体以促进肿瘤增殖。然而，YAP是否刺激另一种促进肿瘤的葡萄糖代谢途径——磷酸戊糖途径（PPP），以及这种刺激与ISGylation之间的关系尚需进一步研究。在此，我们发现YAP发生了ISGylation，这种ISGylation抑制了YAP的泛素化、蛋白酶体降解以及与含β-转导素重复序列的E3泛素蛋白连接酶（βTrCP）的相互作用，从而促进YAP的稳定性。然而，YAP K497R（K，赖氨酸；R，精氨酸）突变消除了ISGylation诱导的促YAP效应，表明K497可能是YAP主要的ISGylation位点。此外，YAP ISGylation促进细胞活力、细胞源性异种移植（CDX）和患者源性异种移植（PDX）肿瘤形成。YAP ISGylation还增加了下游基因的转录，包括PPP的关键酶之一6-磷酸葡萄糖酸内酯酶（6PGL）。机制上，YAP通过同时招募SMAD家族成员2（SMAD2）和TEA结构域转录因子4（TEAD4）结合到6PGL启动子来激活PPP，从而促进6PGL转录。在临床肺腺癌（LUAD）标本中，我们发现YAP ISGylation程度与6PGL mRNA水平呈正相关，尤其是在高糖LUAD组织与低糖LUAD组织相比时。总体而言，本研究表明YAP ISGylation对于维持其稳定性以及进一步激活PPP至关重要。靶向ISGylated YAP可能是高血糖癌症治疗的新选择。
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