Jiang Yanan, Xing Donghui, He Xiang, Wu Wenqi, Xu Hong, Sun Huimeng, Zhai Yixin, Luo Kaiping, Zhao Zhigang
Department of Medical Oncology, School of Medicine, Tianjin First Central Hospital, Nankai University, Tianjin, 300192, China.
Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Tianjin, China.
BMC Cancer. 2025 May 28;25(1):955. doi: 10.1186/s12885-025-14257-y.
Diffuse large B-cell lymphoma (DLBCL) is an aggressive hematopoietic malignancy, necessitating the exploration of innovative therapeutic approaches. Targeting epigenetic mechanisms has emerged as a promising avenue for cancer treatment. EP300 belongs to the KAT3 family of histone/non-histone lysine acetyltransferases, regulating gene expression by acetylating H3K27. However, the role of EP300 and its potential as a targeted therapy in DLBCL remains unknown.
Public datasets were collected to evaluate the expression and clinical significance of epigenetic modification-related genes in patients with DLBCL. Flow cytometry, colony formation, and western blotting were conducted to investigate the function of EP300. CCK8, proliferation, cell cycle, and apoptosis assays, as well as experiments in tumor-bearing mouse models were conducted to determine the therapeutic effect of the EP300 inhibitor A485 alone or in combination with the XPO1 inhibitor KPT8602. RNA-seq was used to investigate the molecular mechanisms underlying the inhibition of DLBCL development by A485.
EP300 is frequently overexpressed in DLBCL and is associated with poor prognosis, highlighting its potential role in lymphoma progression. In this study, we found that A485, a novel small-molecule inhibitor targeting the conserved histone acetyltransferase (HAT) domain of EP300, significantly reduced H3K27Ac levels and demonstrated potent antitumor effects in DLBCL cells, both in vitro and in vivo. Furthermore, we showed that A485 attenuated DLBCL progression by inhibiting the MYC and E2F1 pathways. Notably, the combination of A485 with the XPO1 inhibitor KPT8602 produced synergistic anti-lymphoma in vitro and in vivo effects in DLBCL cell lines. This combination therapy resulted in enhanced tumor suppression in a DLBCL xenograft model with minimal toxicity. These findings suggested that targeting EP300, particularly in conjunction with XPO1 inhibition, could represent a promising therapeutic strategy for DLBCL treatment.
Our study elucidated that EP300 inhibition, especially in combination with XPO1 blockade, could serve as a promising therapeutic strategy for the treatment of DLBCL.
弥漫性大B细胞淋巴瘤（DLBCL）是一种侵袭性造血系统恶性肿瘤，需要探索创新的治疗方法。靶向表观遗传机制已成为癌症治疗的一个有前景的途径。EP300属于组蛋白/非组蛋白赖氨酸乙酰转移酶的KAT3家族，通过乙酰化H3K27来调节基因表达。然而，EP300在DLBCL中的作用及其作为靶向治疗的潜力尚不清楚。
收集公共数据集以评估DLBCL患者中表观遗传修饰相关基因的表达和临床意义。进行流式细胞术、集落形成和蛋白质印迹分析以研究EP300的功能。进行CCK8、增殖、细胞周期和凋亡检测以及荷瘤小鼠模型实验，以确定EP300抑制剂A485单独或与XPO1抑制剂KPT8602联合使用的治疗效果。RNA测序用于研究A485抑制DLBCL发展的分子机制。
EP300在DLBCL中经常过度表达，并与不良预后相关，突出了其在淋巴瘤进展中的潜在作用。在本研究中，我们发现A485是一种靶向EP300保守组蛋白乙酰转移酶（HAT）结构域的新型小分子抑制剂，可显著降低H3K27Ac水平，并在体外和体内对DLBCL细胞显示出强大的抗肿瘤作用。此外，我们表明A485通过抑制MYC和E2F1途径减弱DLBCL进展。值得注意的是，A485与XPO1抑制剂KPT8602联合使用在体外和体内对DLBCL细胞系产生协同抗淋巴瘤作用。这种联合治疗在DLBCL异种移植模型中增强了肿瘤抑制作用，且毒性最小。这些发现表明，靶向EP300，特别是与XPO1抑制联合使用，可能是DLBCL治疗的一种有前景的治疗策略。
我们的研究阐明，抑制EP300，特别是与XPO1阻断联合使用，可作为治疗DLBCL的一种有前景治疗策略。
