Pluripotent Stem Cell Protein Sox2 Confers Sensitivity to LSD1 Inhibition in Cancer Cells
Xiaoming Zhang,
Fei Lu,
Jing Wang,
Feng Yin,
Zhengshuang Xu,
Dandan Qi,
Xianhui Wu,
Yuwen Cao,
Weihua Liang,
Yuqing Liu,
Hong Sun,
Tao Ye,
Hui Zhang
Affiliations
Xiaoming Zhang
College of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China
Fei Lu
College of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China
Jing Wang
College of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China
Feng Yin
College of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China
Zhengshuang Xu
College of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China
Dandan Qi
College of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China
Xianhui Wu
College of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China
Yuwen Cao
Department of Pathology and Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang 832002, China
Weihua Liang
Department of Pathology and Key Laboratory of Xinjiang Endemic and Ethnic Diseases, Shihezi University School of Medicine, Shihezi, Xinjiang 832002, China
Yuqing Liu
Department of Applied Biology and Chemical Technology, Hong Kong Polytechnic University, Kowloon, Hong Kong, China
Hong Sun
Department of Chemistry, University of Nevada at Las Vegas, 4505 S. Maryland Parkway, Las Vegas, NV 89154-4003, USA
Tao Ye
Department of Applied Biology and Chemical Technology, Hong Kong Polytechnic University, Kowloon, Hong Kong, China
Hui Zhang
College of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China
Gene amplification of Sox2 at 3q26.33 is a common event in squamous cell carcinomas (SCCs) of the lung and esophagus, as well as several other cancers. Here, we show that the expression of LSD1/KDM1 histone demethylase is significantly elevated in Sox2-expressing lung SCCs. LSD1-specific inhibitors selectively impair the growth of Sox2-expressing lung SCCs, but not that of Sox2-negative cells. Sox2 expression is associated with sensitivity to LSD1 inhibition in lung, breast, ovarian, and other carcinoma cells. Inactivation of LSD1 reduces Sox2 expression, promotes G1 cell-cycle arrest, and induces genes for differentiation by selectively modulating the methylation states of histone H3 at lysines 4 (H3K4) and 9 (H3K9). Reduction of Sox2 further suppresses Sox2-dependent lineage-survival oncogenic potential, elevates trimethylation of histone H3 at lysine 27 (H3K27) and enhances growth arrest and cellular differentiation. Our studies suggest that LSD1 serves as a selective epigenetic target for therapy in Sox2-expressing cancers.
