Targeting the LSD1-G9a-ER Stress Pathway as a Novel Therapeutic Strategy for Esophageal Squamous Cell Carcinoma.
Hongxiao WangZijun SongEnjun XieJunyi ChenBiyao TangFudi WangJunxia MinPublished in: Research (Washington, D.C.) (2022)
Despite recent advances in the management and treatment of esophageal squamous cell carcinoma (ESCC), the prognosis remains extremely poor, and current nonsurgical treatment options are limited. To identify new therapeutic targets, we screened a curated library of epigenetic compounds using a panel of cancer cell lines and found that coinhibiting the histone demethylase LSD1 and the histone methyltransferase G9a potently suppresses cell growth; similar results were obtained by knocking down both LSD1 and G9a expression. Importantly, we also found that inhibiting LSD1 and G9a significantly decreased tumor growth in a xenograft mouse model with ESCC cell lines. To examine the clinical relevance of these findings, we performed immunohistochemical analyses of microarray profiling data obtained from human esophageal squamous cancer tissues and found that both LSD1 and G9a are upregulated in cancer tissues compared to healthy tissues, and this increased expression was significantly correlated with poor prognosis. Mechanistically, we discovered that inhibiting LSD1 and G9a induces cell death via S-phase arrest and apoptosis, and cotargeting ER stress pathways increased this effect both in vitro and in vivo . Taken together, these findings provide compelling evidence that targeting LSD1, G9a, and ER stress-related pathways may serve as a viable therapeutic strategy for ESCC.
Keyphrases
- poor prognosis
- papillary thyroid
- cell death
- long non coding rna
- gene expression
- dna methylation
- mouse model
- signaling pathway
- squamous cell
- endothelial cells
- oxidative stress
- lymph node metastasis
- cancer therapy
- machine learning
- cell cycle
- single cell
- binding protein
- squamous cell carcinoma
- drug delivery
- combination therapy
- artificial intelligence
- data analysis
- induced pluripotent stem cells