Targeting EP300 in diffuse large b-cell lymphoma: efficacy of A485 and synergistic effects with XPO1 inhibition.

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusions: Our study elucidated that EP300 inhibition, especially in combination with XPO1 blockade, could serve as a promising therapeutic strategy for the treatment of DLBCL.