YAP promotes autophagy and progression of gliomas via upregulating HMGB1.
YAP promotes autophagy and progression of gliomas via upregulating HMGB1.
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YAP 通过上调 HMGB1 促进神经胶质瘤的自噬和进展
DOI：
10.1186/s13046-021-01897-8
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发表时间：
2021-03-16
期刊：
影响因子：
--
通讯作者：
Zhou X
中科院分区：
文献类型：
--
作者：
Zhao M;Zhang Y;Jiang Y;Wang K;Wang X;Zhou D;Wang Y;Yu R;Zhou X
研究背景胶质母细胞瘤（glioblastoma，GBM）由于缺氧和营养缺乏的微环境，表现出较高的自噬活性，自噬在GBM的发生发展中起重要作用。然而，自噬在GBM进展中的分子机制仍不清楚。本研究旨在探讨yes相关蛋白（雅普）在GBM自噬及进展中的作用和机制。方法采用免疫印迹、GFP-LC 3斑点（Live）成像、透射电镜和GFP-RFP-LC 3分析等方法检测GBM自噬水平或自噬流量。采用CCK 8、EdU、裸鼠移植瘤及Ki 67染色检测GBM进展情况。采用同位素标记相对和绝对定量（iTraq）定量蛋白质组学方法，研究自噬过程中雅普的调节机制。雅普和HMGB 1的表达水平从GBM患者的组织样本进行了检查，通过Western印迹，组织芯片和免疫组化ResultsYAP过度表达增强胶质瘤细胞自噬的基础和诱导条件下。氯喹阻断自噬后，雅普对胶质瘤生长的促进作用消失。机制上，雅普过表达促进高迁移率族蛋白1（HMGB 1）的转录和易位，HMGB 1是一种众所周知的自噬调节剂，从细胞核到细胞质。下调HMGB 1表达可阻断雅普对自噬和胶质瘤生长的促进作用。结论YAP通过增强HMGB 1介导的自噬作用促进胶质瘤的进展，提示YAP-HMGB 1轴是治疗胶质瘤的一个可行靶点。我们的研究揭示了一个临床机会，涉及化疗-放疗与药物自噬抑制的组合，用于治疗雅普高表达的GBM患者。
BackgroundDue to the hypoxia and nutrient deficiency microenvironment, glioblastoma (GBM) exhibits high autophagy activity and autophagy plays an important role in the progression of GBM. However, the molecular mechanism of autophagy in GBM progression remains unclear. The aim of this study is to delve out the role and mechanism of yes-associated protein (YAP) in GBM autophagy and progression.MethodsThe level of autophagy or autophagy flux were assessed by using western blotting, GFP-LC3 puncta (Live) imaging, transmission electron microscopy and GFP-RFP-LC3 assay. The GBM progression was detected by using CCK8, EdU, nude mouse xenograft and Ki67 staining. Isobaric tags for relative and absolute quantification (iTraq) quantitative proteomics was used to find out the mediator of YAP in autophagy. Expression levels of YAP and HMGB1 in tissue samples from GBM patients were examined by Western blotting, tissue microarray and immunohistochemistry.ResultsYAP over-expression enhanced glioma cell autophagy under basal and induced conditions. In addition, blocking autophagy by chloroquine abolished the promoting effect of YAP on glioma growth. Mechanistically, YAP over-expression promoted the transcription and translocation of high mobility group box 1(HMGB1), a well-known regulator of autophagy, from nucleus to cytoplasm. Down-regulation of HMGB1 abolished the promoting effect of YAP on autophagy and glioma growth. Furthermore, the expression of YAP and HMGB1 were positively associated with each other and suggested poor prognosis for clinical GBM.ConclusionYAP promoted glioma progression by enhancing HMGB1-mediated autophagy, indicating that YAP-HMGB1 axis was a feasible therapeutic target for GBM. Our study revealed a clinical opportunity involving the combination of chemo-radiotherapy with pharmacological autophagy inhibition for treating GBM patients with YAP high expression.
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影响因子：
82.9
作者：
通讯作者：
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YAP 增强自噬通量以促进乳腺癌细胞在营养缺乏时的存活
影响因子：
3.7
作者：
Song Q;Mao B;Cheng J;Gao Y;Jiang K;Chen J;Yuan Z;Meng S
通讯作者：
Meng S
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影响因子：
9.7
作者：
Jiang, Tao;Mao, Ying;Wang, Qixue
通讯作者：
Wang, Qixue
影响因子：
11.2
作者：
Hu YL;Jahangiri A;Delay M;Aghi MK
通讯作者：
Aghi MK
影响因子：
16.6
作者：
Pavel M;Renna M;Park SJ;Menzies FM;Ricketts T;Füllgrabe J;Ashkenazi A;Frake RA;Lombarte AC;Bento CF;Franze K;Rubinsztein DC
通讯作者：
Rubinsztein DC