SIRT6对APLNR信号通路的调控在弥漫大B细胞淋巴瘤发生发展中的作用机制

尽管免疫化疗已改善了弥漫大B细胞淋巴瘤（DLBCL）的预后，但仍有1/3患者难治复发。近来，组蛋白去乙酰化酶抑制剂的抗肿瘤作用备受关注，但在DLBCL中的应用仍有局限性。我们前期研究发现组蛋白去乙酰化酶SIRT6异常表达与DLBCL不良预后显著相关，然而，其下游调控机制仍不甚清。另外预实验证实敲减DLBCL中SIRT6表达后，APLNR信号显著差异表达。本项目拟在前期研究基础上，结合DLBCL临床样本大数据平台、CUT&Tag及PDX动物模型等新型技术，深入探讨SIRT6异常表达在DLBCL中的临床意义；明确SIRT6对DLBCL细胞生物学行为的干预作用；阐明SIRT6介导组蛋白去乙酰化调控APLNR信号的分子机制；构建动物模型体内验证SIRT6抑制剂OSS_128167的抗肿瘤效应。预期研究成果将揭示SIRT6在DLBCL发生发展中的调控机制，为DLBCL个体化诊疗提供新思路和理论依据。

Although immunochemotherapy has significantly improved the prognosis of diffuse large B-cell lymphoma (DLBCL), there are still approximately 1/3 of them presented refractory or recurrent process. Recently, the anti-tumor effect of histone deacetylase (HDAC) inhibitors has become a hotspot. However, the application of HDAC inhibitors in DLBCL still has limitations. SIRT6, a member of the Sirtuin family which also called class III HDACs, plays a pivotal role in the pathogenesis of several tumors. In the previous study, we discovered the aberrant expression of SIRT6 in DLBCL tissues and cell lines. High expression of SIRT6 was significantly related to poor prognosis of DLBCL. However, the regulatory mechanism of SIRT6 in DLBCL remains unclear. Our previous experiments confirmed that SIRT6 knockdown in DLBCL resulted in significant inhibition of APLNR signaling pathway. Based on above studies, this study aims to investigate the role of SIRT6 in the pathogenesis of DLBCL in the following aspects: Firstly, we will investigate the expression status and clinical significance of SIRT6 in DLBCL based on clinical sample library and big data platform. Secondly, the function of SIRT6 on the proliferation, apoptosis and cell cycle of DLBCL cells will be examined via CRISPR/Cas9 genomic editing system. Besides, the regulatory mechanisms of SIRT6 on histone acetylation site and APLNR signaling will then be verified by CUT&Tag and luciferase reporter technologies. Lastly, the in vivo antitumor effect of the SIRT6 specific inhibitor OSS_128167 will be verified using PDX mice model. The finding of this study will uncover the mechanisms of SIRT6 in the development, progression and targeted intervention of DLBCL, and provide novel theoretical and experimental basis to improve the prognosis of DLBCL.