Abstract 192P
Background
Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy with limited treatment options, leading to poor 5-year survival rates. This study investigates the repurposing potential of Niclosamide, focusing on its ability to modulate epigenetic targets to enhance chemosensitivity in ESCC.
Methods
To identify potential targets, we analyzed RNA expression data and Niclosamide-mediated cell survival rates using publicly available data from twenty-three ESCC cell lines. Findings were validated in three ESCC cell lines (CE81T2, OE21, KYSE270) through cytotoxicity assays, mRNA expression quantification, and Western blot analysis, along with the use of STAT3 and c-Myc inhibitors. The TCGA dataset was also utilized to assess overall survival and progression-free survival.
Results
Our analysis revealed significant correlations between the RNA expressions of 459 genes and Niclosamide treatment, with 204 showing negative correlations. Among these, 76.0% (156 genes) were STAT3 targets. EHMT2 (G9a), a histone H3K9 and H3K27 methyltransferase, emerged as a potential modulator of Niclosamide within the STAT3 targets. In vitro studies demonstrated increased Niclosamide sensitivity in metastatic daughter cell lines and dose-dependent downregulation of EHMT2 RNA and protein levels post-Niclosamide treatment, with LC3II induction unaffected by chloroquine or MG132 co-treatment. This suggests that both autophagy and proteasome degradation systems are dispensable for Niclosamide-mediated EHMT2 reduction. Furthermore, the suppression of EHMT2 by Niclosamide involve both STAT3 and c-Myc pathways, as indicated by the use of specific inhibitors BBI-608 and 10058-F4. TCGA data revealed poorer overall survival rates in ESCC patients with high EHMT2 and c-Myc expression (p=0.026), though no significant differences in progression-free survival were observed (p=0.78).
Conclusions
Our combined in silico and in vitro findings propose EHMT2 as a potential epigenetic regulator under the STAT3 and c-Myc axis in ESCC, warranting further exploration and validation in vivo and clinically.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Kaohsiung Medical University; Kaohsiung Medical University Hospital.
Disclosure
All authors have declared no conflicts of interest.