title: Pluripotent stem cell protein Sox2 confers sensitivity to LSD1 inhibition in cancer cells.
abstract: 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.
authors.affiliation: College of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, Guangdong 518055, China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zhang
authors.forename: Fei
authors.initials: F
authors.lastname: Lu
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.forename: Feng
authors.initials: F
authors.lastname: Yin
authors.forename: Zhengshuang
authors.initials: Z
authors.lastname: Xu
authors.forename: Dandan
authors.initials: D
authors.lastname: Qi
authors.forename: Xianhui
authors.initials: X
authors.lastname: Wu
authors.forename: Yuwen
authors.initials: Y
authors.lastname: Cao
authors.forename: Weihua
authors.initials: W
authors.lastname: Liang
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Liu
authors.forename: Hong
authors.initials: H
authors.lastname: Sun
authors.forename: Tao
authors.initials: T
authors.lastname: Ye
authors.forename: Hui
authors.initials: H
authors.lastname: Zhang
mesh_terms: D002454:Cell Differentiation; D045744:Cell Line, Tumor; D019175:DNA Methylation; D059585:G1 Phase Cell Cycle Checkpoints; D056466:Histone Demethylases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D061986:MCF-7 Cells; D039904:Pluripotent Stem Cells / Q000166:cytology / Q000378:metabolism; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D006657:Histones; D034741:RNA, Small Interfering; D055748:SOXB1 Transcription Factors; D056466:Histone Demethylases; C495195:KDM1A protein, human