Thioredoxin-interacting protein-activated intracellular potassium deprivation mediates the anti-tumour effect of a novel histone acetylation inhibitor HL23, a fangchinoline derivative, in human hepatocellular carcinoma

• DOI: 10.1016/j.jare.2022.10.017
• Publication Date: 2022-11-06T16:31:29Z
• Authors: Yuanjun Lu; Yazhou Liu; Junjie Lan; Yau-Tuen Chan; Zixin Feng; Lan Huang; Ning Wang; Weidong Pan; Yibin Feng
• Keywords: Derivative (finance)

Hyperactivated histone deacetylases (HDACs) act as epigenetic repressors on gene transcription and are frequently observed in human hepatocellular carcinoma (HCC). Although multiple pharmacological HDAC inhibitors (HDACis) have been developed, none is available HCC.To investigate the effects of a fangchinoline derivative HL23, novel HDACi its molecular mechanisms through TXNIP-mediated potassium deprivation HCC.Both vitro assays orthotopic HCC mouse models were used to HL23 this study. The inhibitory activity HDACs was evaluated by silico studies cellular assays. Chromatin immunoprecipitation (ChIP) conducted confirm regulation acetylation mark at TXNIP promoter. Genome-wide transcriptome analysis together with bioinformatic identify regulatory HL23. clinical significance analysing publicly database.HL23 exerted compatible inhibition potency Vorinostat (SAHA) while had superior anti-HCC than SAHA sorafenib. Both vivo showed significantly suppressed progression metastasis. upregulated expression via regulating (H3K9ac) responsible for mediating channel activity. HDAC1 predicted be target HDAC1lowTXNIPhigh could jointly predict promising survival outcome patients HCC. Combination treatment sorafenib enhance efficacy.Our study identified enhancing promoter trigger TXNIP-dependent efficacy treatment.