Abstract

Diffuse large B-cell lymphoma (DLBCL) is an aggressive hematologic malignancy with complex pathogenesis and unsatisfactory clinical outcomes. Although histone deacetylase inhibitors (HDACis) have demonstrated therapeutic potential, the molecular mechanisms linking epigenetic regulation to key oncogenic signaling pathways remain incompletely understood. In this study, B-cell translocation gene 1 (BTG1) was identified as a critical tumor suppressor that is epigenetically upregulated by HDAC inhibition in DLBCL cells. Increased BTG1 expression was found to be both necessary and sufficient for HDAC inhibitor–induced cell cycle arrest and autophagy, whereas BTG1 silencing attenuated these effects. Mechanistically, BTG1 suppressed β-catenin signaling by inhibiting the formation of the β-catenin/TCF4 transcriptional complex, leading to reduced expression of downstream targets, including c-Myc and Cyclin D1 . Activation of β-catenin signaling reversed the tumor-suppressive effects of BTG1, supporting the functional importance of this pathway. In vivo, the antitumor efficacy of HDAC inhibition in DLBCL xenografts was dependent on the BTG1/β-catenin axis. Collectively, these findings identify a regulatory link between HDAC inhibition and β-catenin signaling mediated by BTG1, providing mechanistic insight into HDAC inhibitor–based therapy in DLBCL.