2. Academic Validation
  3. 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

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

  • J Adv Res. 2023 Sep:51:181-196. doi: 10.1016/j.jare.2022.10.017.
Yuanjun Lu 1,  Yazhou Liu 2,  Junjie Lan 3,  Yau-Tuen Chan 1,  Zixin Feng 1,  Lan Huang 1,  Ning Wang 4,  Weidong Pan 5,  Yibin Feng 6
Affiliations

Affiliations

  • 1 School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong.
  • 2 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Science, Guiyang 550014, China; Natural Products Research Centre, Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China.
  • 3 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Science, Guiyang 550014, China.
  • 4 School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong. Electronic address: [email protected].
  • 5 State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, Guiyang 550014, China; The Key Laboratory of Chemistry for Natural Products of Guizhou Province and Chinese Academy of Science, Guiyang 550014, China. Electronic address: [email protected].
  • 6 School of Chinese Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong. Electronic address: [email protected].
PMID: 36351536 DOI: 10.1016/j.jare.2022.10.017
Abstract

Introduction: 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 in human HCC.

Objectives: To investigate the pharmacological effects of a fangchinoline derivative HL23, as a novel HDACi and its molecular mechanisms through TXNIP-mediated potassium deprivation in HCC.

Methods: Both in vitro assays and orthotopic HCC mouse models were used to investigate the effects of HL23 in this study. The inhibitory activity of HL23 on HDACs was evaluated by in silico studies and cellular assays. Chromatin immunoprecipitation (ChIP) was conducted to confirm the regulation of HL23 on acetylation mark at TXNIP promoter. Genome-wide transcriptome analysis together with bioinformatic analysis were conducted to identify the regulatory mechanisms of HL23. The clinical significance of TXNIP and HDACs was evaluated by analysing publicly available database.

Results: HL23 exerted compatible HDACs inhibition potency as Vorinostat (SAHA) while had superior anti-HCC effects than SAHA and sorafenib. Both in vitro and in vivo studies showed HL23 significantly suppressed HCC progression and metastasis. HL23 significantly upregulated TXNIP expression via regulating acetylation mark (H3K9ac) at TXNIP promoter. TXNIP was responsible for anti-HCC activity of HL23 through mediating Potassium Channel activity. HDAC1 was predicted to be the target of HL23 and HDAC1lowTXNIPhigh could jointly predict promising survival outcome of patients with HCC. Combination treatment with HL23 and sorafenib could significantly enhance sorafenib efficacy.

Conclusion: Our study identified HL23 as a novel HDACi through enhancing acetylation at TXNIP promoter to trigger TXNIP-dependent potassium deprivation and enhance sorafenib efficacy in HCC treatment.

Keywords

HDAC; Hepatocellular carcinoma; Potassium deprivation; Sorafenib; TXNIP.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-155248
    HDAC Inhibitor