KAT5调控TNFRSF10B乙酰化与转录在DLBCL发病中的作用与机制

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.

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。

弥漫大B细胞淋巴瘤（DLBCL）是最常见的淋巴瘤类型，侵袭性高，随着R-CHOP等免疫化疗方案的应用，DLBCL的生存率得到很大改善，但仍有30-40%的患者对治疗不耐受或治疗后复发，且DLBCL发病机制未完全阐明，因此研究DLBCL的发病机制，寻找DLBCL治疗的新的靶点和特异性药物非常重要。凋亡逃逸是DLBCL发病的关键因素之一，因此本项目研究了死亡受体TNFRSF10B在DLBCL细胞中的表达及其对DLBCL细胞凋亡的作用。结果显示多种化疗药物均可诱导TNFRSF10B的表达增强，TNFRSF10B表达促进了DLBCL细胞凋亡。同时实验发现TNFRSF10B存在乙酰化修饰；去乙酰化酶抑制剂增强了细胞中乙酰化水平，促进TNFRSF10B表达，并通过ATF3和DDIT3调控TNFRSF10B的转录和表达；体内实验也表明增强细胞的乙酰化水平能一定程度上抑制DLBCL肿瘤细胞的增殖。另外课题发现乙酰转移酶KAT5在DLBCL中表达偏高，且与DLBCL生存率呈负相关性；但是KAT5表达可能对DLBCL小鼠成瘤影响不是很显著。KAT5抑制剂NU9056抑制DLBCL细胞增殖，诱导DLBCL细胞周期阻滞，并通过ATF3、DDIT3促进细胞凋亡，同时影响细胞中JAK/STAT和MAPK信号通路。本项目的实验结果将为理解DLBCL发病机制，探索新的治疗靶点，设计、开发治疗DLBCL的新型药物提供实验依据。

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