化疗耐受是胶质瘤术后复发的重要原因，其发生与内质网应激（ERS）诱导的凋亡受阻密切相关，但机制不明。我们前期发现，胶质瘤细胞耐药产生会伴有组蛋白去乙酰化酶6（HDAC6）表达上调，ERS感受器PERK活化减弱引起的凋亡通路失活；而敲低HDAC6可重启ERS凋亡通路，恢复细胞对化疗的敏感性。我们推测，HDAC6是调节ERS的重要“开关”，其改变是影响ERS凋亡通路的开启和关闭以及胶质瘤耐药的关键因素。本项目拟：1) 敲低或过表达HDAC6，解析其在阻遏ERS凋亡通路激活及导致胶质瘤耐药产生的作用；2）通过基因定点突变，探讨HDAC6去乙酰化结构域及泛素结合功能域对ERS感受器及相关信号通路的影响，阐明HDAC6调控ERS“开与关”及胶质瘤耐药的分子机制；3）在裸鼠原位瘤移植模型验证HDAC6对ERS及胶质瘤耐药的调控作用。本研究有望为阐明胶质瘤耐药的分子机制及寻找新的治疗靶点提供实验依据。

Endoplasmic reticulum stress (ERS) tolerance is an important cause of glioma chemoresistance, but the mechanism remains unclear. We have recently shown that glioma chemoresistance concurrently occurs with histone deacetylase 6 (HDAC6) upregulation and the shut-off of ERS response, while knockdown of HDAC6 reactivates ERS response and the reduction in chemoresistance, which is accompanied by corresponding changes in the activation of ERS sensor (or initiator) protein PERK. Our data and the fact that HDAC6 can regulate PERK activation via deacetylation of glucose-regulated protein 78 (GRP78) have led to the formation of the central hypothesis of this project that HDAC6 works as an “on-and-off” switch protein of ERS response to regulate glioma chemoresistance and its upregulation can lead to ERS sensor inactivation, the blockade of the initiation of ERS response and eventually the occurrence of chemoresistance. We have developed the following three specific aims to test our hypothesis: 1) we will determine whether HDAC6 plays a critical role in the regulation of ERS response and chemoresistance in glioma cells challenged by chemotherapy via knocking down and overexpressing HDAC6; 2) we will determine how HDAC6 interacts with ERS sensors to regulate ERS response and chemoresistance via gene point mutation for the deacetylase domain and the ubiquitinized protein binding domain of HDAC6; and 3) we will further verify that HDAC6 plays a critical role in regulating ERS associated apoptosis and chemoresistance on an in situ glioma rude mouse model. The completion of this study will not only uncover the molecular mechanism underlying glioma chemoresistance, but will also help with identifying new targets for glioma therapy.