自噬可介导多种肿瘤EMT和放化疗抵抗，但机制不明。我们已证实替莫唑胺（TMZ）能诱导GBM细胞自噬并上调E3连接酶HERC3，泛素化降解SMAD7，激活SMAD2/3依赖的TGF-β通路并介导EMT。深入研究显示上述作用受FOXK1调控，而HDACi抑制其表达并逆转HERC3作用，但甲基化抑制剂作用相反。进一步发现H3K4me3/H3K36me3能促进NFIC(K69ac)和FOXK1结合并抑制其表达，该过程受去甲基化酶RSBN1（受自噬上调）和乙酰化转移酶EP300（受自噬下调）调节。生存分析显示NFIC低、FOXK1高表达GBM病例，TMZ放化疗预后较差。故我们推测：TMZ诱导GBM自噬，进而通过RSBN1和EP300调控NFIC(K69ac)/FOXK1/HERC3信号轴的PTM，激活TGF-β通路，促进了EMT和治疗抵抗。本课题拟探明上述机制，以期为GBM放化疗抵抗提供治疗靶点。

Autophagy reportedly contributes indispensably to induce epithelial-to-mesenchymal transition (EMT) and chemo radio-resistance of several cancers, while the mechamism remains unkonwn. Our preliminary work proved that autophagy induced by Temezolomide (TMZ) upregulates E3 ligase HERC3, then activates the SMAD2/3-dependent TGF-β signaling pathway and mediates EMT by ubiquitin-mediated degradation of SMAD7. Further studies indicated that EMT induced by HERC3 is regulated by FOXK1 level. Moreover, histone deacetylase inhibitor (HDACi) inhibites the expression of FOXK1 and reverses the function of HERC3. However, methylation inhibitor up-regulates FOXK1 level and promotes the activation of TGF-β signaling pathway and EMT. In addtion, H3K4me3/H3K36me3 is found to promote the binding of NFIC(K69ac) to FOXK1 promoter, and transcriptionally inhibits FOXK1 expression. This biological process is regulated by RSBN1 (Lysine-specific demethylase 9), which is upregulated by autophagy; and EP300 (Histone acetyltransferase p300), which is downregulated by autophagy. Kaplan meier survival analysis based on TCGA database also indicates that GBM cases with low NFIC and high FOXK1 level have poor prognosis with undergone TMZ chemo-radiotherapy. So we propose the hypothesis that autophagy induced by TMZ regulates the expression of RSBN1 and EP300, which promotes the demethylation of H3K4me3/H3K36me3 and deacytalation of NFIC(K69ac) to regulate the expression of key moleculars in NFIC(K69ac)/FOXK1/HERC3 signaling axis, and finally activates the TGF-β pathway. Consequently, EMT and chemoradio-resistance occurres. This stduy takes the aim to investigate and prove the above molecular mechanism in details, and is hoping to provide the experimental evidence and molecular-based therapeutic targets for GBM chemoradio-therapy resistant.