KAT5调控TNFRSF10B乙酰化与转录在DLBCL发病中的作用与机制

弥漫大B细胞淋巴瘤（DLBCL）是一种侵袭性恶性肿瘤，难治、复发率较高，且发病机制未完全阐明。凋亡逃逸是DLBCL发病的关键因素之一，而死亡受体TNFRSF10B低表达是DLBCL凋亡逃逸的一个重要原因，但其表观遗传修饰机制所知甚少。我们前期发现多种化疗药物明显提高DLBCL细胞中TNFRSF10B和乙酰转移酶KAT5表达，且TNFRSF10B发生乙酰化并结合KAT5；同时我们发现KAT5影响TNFRSF10B转录。因此我们提出假说：KAT5调控TNFRSF10B乙酰化与转录，进而促进细胞凋亡，抑制DLBCL发生发展。本项目拟进一步明确TNFRSF10B的乙酰化修饰，探明其乙酰化修饰对凋亡通路的调控；同时体外、体内实验阐明KAT5通过调控TNFRSF10B影响DLBCL发生发展的机制。若获成功，可加深对DLBCL发病的认识，为设计、开发治疗DLBCL的特异性靶向药物提供新实验基础。

Diffuse large B cell lymphoma (DLBCL) is a kind of aggressive malignant tumor, whose pathogenesis mechanisms still remain unclear. A substantial number of DLBCL patients is either refractory or relapse following initial therapy. Apoptosis escape is one of the hallmarks in the pathogenesis of DLBCL, and the low expression of TNFRSF10B is a crucial reason for the apoptosis escape in DLBCL. However, the epigenetic modification of TNFRSF10B is not very clear. Our pre-experimental results found that a variety of chemotherapy drugs significantly increased the expression of TNFRSF10B and acetyltransferase KAT5 in DLBCL cells，and TNFRSF10B is acetylated and interacted with KAT5. In the other hand, we found that KAT5 regulated TNFRSF10B transcription unexpected. Therefore, we propose the hypothesis that KAT5 regulates TNFRSF10B acetylation and transcription, then promotes apoptosis and inhibits DLBCL oncogenesis. In this project, we will further confirm the regulation of TNFRSF10B by acetylation, elucidate the regulationary mechanisms of TNFRSF10B acetylation on apoptotic pathway, and clarify the mechanism of KAT5 via regulating TNFRSF10B in DLBCL oncogenesis both in vitro and vivo. If successful, this study may deepen the understanding of the pathogenesis of DLBCL and provide new theoretical support for the development of novel therapeutic targeted drugs.