Targeting the LSD1-G9a-ER Stress Pathway as a Novel Therapeutic Strategy for Esophageal Squamous Cell Carcinoma

Hongxiao Wang; Zijun Song; Enjun Xie; Junyi Chen; Biyao Tang; Fudi Wang; Junxia Min

doi:10.34133/2022/9814652

Targeting the LSD1-G9a-ER Stress Pathway as a Novel Therapeutic Strategy for Esophageal Squamous Cell Carcinoma

Research (Wash D C). 2022 Jun 1:2022:9814652. doi: 10.34133/2022/9814652. eCollection 2022.

Authors

Hongxiao Wang^{1

2

3}, Zijun Song¹, Enjun Xie¹, Junyi Chen¹, Biyao Tang¹, Fudi Wang^{1

2}, Junxia Min¹

Affiliations

¹ The First Affiliated Hospital, The Fourth Affiliated Hospital, Institute of Translational Medicine, School of Public Health, Cancer Center, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou 310058, China.
² The First Affiliated Hospital, The Second Affiliated Hospital, Basic Medical Sciences, School of Public Health, School of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang 421001, China.
³ Department of Pathology, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, People's Hospital of Henan University, Zhengzhou 450003, China.

Abstract

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.