YAP通过快速与长效双重机制促进脑胶质瘤自噬与增殖的研究

脑胶质瘤处于颅内缺氧缺糖的微环境，自噬水平较高，自噬在促进脑胶质瘤的恶性进展中起着重要作用，但调控机制不清。我们发现YAP促进基础及诱导后的自噬；过表达YAP上调并促进HMGB1快速转位到细胞浆，下调HMGB1抑制自噬并阻断YAP促进自噬的作用。此外，持续激活突变体YAP5SA的作用强于YAPWT；促进自噬的分子PLAC8的核酸及蛋白水平在过表达YAP后明显升高，且其启动子与TEAD有潜在结合位点。综上，我们提出“YAP一方面通过促进HMGB1快速转位到细胞浆，同时通过促进PLAC8的转录，共同维持肿瘤细胞的高自噬水平”的科学假说。本项目将从分子、细胞与在体水平阐明YAP通过快速（非转录）和长效（转录）双重机制促进脑胶质瘤自噬与增殖的作用，为临床高表达YAP的GBM患者采取靶向YAP的分子治疗或自噬抑制剂联合放化疗的个性化综合治疗措施提供新的思路。

Due to the hypoxia and nutritional deficiency microenvironment, glioblastoma cells undergo high autophagy activity to support their survival. However, the molecular mechanism of the autophagy in GBM remains largely unknown. We previously find that YAP enhances the autophagy activity under basal or rapamycin-induced conditions. Both iTraq and western blotting results found that YAP up-regulated the protein level of HMGB1, which is closely related with autophagy, and promoted the translocation of HMGB1 from nucleus to cytoplasma. In addition, down-regulation of HMGB1 inhibited autophagy and blocked the promoting effect of YAP on autophagy. Furthermore, the constitutively active mutant YAP5SA has stronger promotion effect on autophagy than that of YAPWT. RNAseq analysis identified that, after YAP over-expression, the mRNA and protein level of PLAC8, which speeds autophagy by promoting autolysosome formation, increased strikingly. More interestingly, YAP-TEAD has three potential binding sites on the promoter region of this gene, indicating that PLAC8 may be the unidentified target gene of YAP. Together, we propose that YAP up-regulates cell autophagy activity by promoting the cytosol translocation of HMGB1 and the transcription of PLAC8 to maintain the high autophagy activity. In the current study, we aimed to explore the effect of YAP, by fast (protein level) and sustained (transcription level) molecular mechanism, on autophagy and glioma progression. Our results will provide valuable ideas, for GBM patients with high YAP level, to designing comprehensive personalized treatment by targeting YAP and/or combining autophagy inhibition using CQ and traditional chemoradiotherapy.