YAP promotes autophagy and progression of gliomas via upregulating HMGB1

Journal of Experimental & Clinical Cancer Research - Tập 40 Số 1 - 2021
Min Zhao1,2,3, Yu Zhang1,2,3, Yang Jiang1,2,4,3, Kai Wang1,2,3, Xiang Wang1,2,3, Ding Zhou1,2,3, Xiaogang Wang1,2,3, Rutong Yu1,2, Xiuping Zhou1,2
1Department of Neurosurgery, Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
2Institute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, China
3The Graduate School, Xuzhou Medical University, Xuzhou, China
4Present address: Clinical Medical College, Yangzhou University, Yangzhou, China

Tóm tắt

Abstract Background Due 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. Methods The 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. Results YAP 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. Conclusion YAP 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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Journal of Experimental & Clinical Cancer Research

Tập 40 Số 1

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