HDAC2 as a therapeutic target in bladder cancer: insights into the altered epigenetic regulation and lysine lactylation

作者：Guanghui Xu, Shuo Liang, Guang Hu, Wei Zhao, Yuqin Li, Minghao Zheng, Zhigang Wu, Tianlei Xie, Shuting Fang, Shan Peng, Yongming Deng, Yihua Zhou, Hongqian Guo, Junlong Zhuang, Wenli Diao · 发表于：Journal of Experimental & Clinical Cancer Research · 年份：2025 · DOI：10.1186/s13046-025-03610-5 · 被引用次数：8 · 研究领域：Histone Deacetylase Inhibitors Research、Epigenetics and DNA Methylation、Peptidase Inhibition and Analysis

BACKGROUND: The pathogenesis of bladder cancer (BCa) is driven in part by aberrant epigenetic regulation, most notably the dysregulated expression of histone deacetylases (HDACs). As a class I HDAC, HDAC2 is often overexpressed in cancers and promotes malignancy through diverse mechanisms. Given its broad oncogenic role, an in-depth investigation of its specific functions in epigenetic and post-translational regulation within BCa holds significant promise for developing novel precision therapies. METHODS: In vitro functional assays, including CCK-8, colony formation, transwell and apoptotic assays, as well as in vivo assays in a nude mouse subcutaneous tumor model, were performed to assess the oncogenic and drug-resistant effects of HDAC2. RNA-seq and ATAC-seq were employed to analyze the epigenetic regulatory mechanisms of HDAC2. Combined proteome, lactylome and acetylome analysis of control and HDAC2-overexpressing BCa cells were conducted to map the global profiling of protein lysine acetylation (Kac) and lactylation (Kla). RESULTS: In vitro and in vivo experiments confirmed that HDAC2 overexpression significantly promoted proliferation, metastasis and chemoresistance of BCa. Integrated RNA-seq and ATAC-seq analysis revealed that HDAC2 overexpression led to significant epigenetic alternations, and knockdown of its downstream GRIK2 significantly reversed the oncogenic effects of HDAC2. We screened class I HDACs for their impact on Kac and Kla in BCa cells and found that HDA...