Pluripotent Stem Cell Protein Sox2 Confers Sensitivity to LSD1 Inhibition in Cancer Cells

被引：102

作者：

Zhang, Xiaoming ^{[1
]}

Lu, Fei ^{[1
]}

Wang, Jing ^{[1
]}

Yin, Feng ^{[1
]}

Xu, Zhengshuang ^{[1
]}

Qi, Dandan ^{[1
,5
]}

Wu, Xianhui ^{[1
]}

Cao, Yuwen ^{[2
,3
]}

Liang, Weihua ^{[2
,3
]}

Liu, Yuqing ^{[4
]}

Sun, Hong ^{[5
]}

Ye, Tao ^{[4
]}

Zhang, Hui ^{[1
,5
]}

机构：

[1] Peking Univ, Coll Chem Biol & Biotechnol, Shenzhen Grad Sch, Shenzhen 518055, Guangdong, Peoples R China

[2] Shihezi Univ, Sch Med, Dept Pathol, Shihezi 832002, Xinjiang, Peoples R China

[3] Shihezi Univ, Sch Med, Key Lab Xinjiang Endem & Ethn Dis, Shihezi 832002, Xinjiang, Peoples R China

[4] Hong Kong Polytech Univ, Dept Appl Biol & Chem Technol, Kowloon, Hong Kong, Peoples R China

[5] Univ Nevada, Dept Chem, Las Vegas, NV 89154 USA

来源：

CELL REPORTS | 2013年 / 5卷 / 02期

基金：

中国国家自然科学基金; 美国国家卫生研究院;

关键词：

GENE-EXPRESSION; LUNG; DIFFERENTIATION; CARCINOMAS; MUTATIONS; ONCOGENE; ROLES;

D O I：

10.1016/j.celrep.2013.09.018

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：445 / 457

页数：13

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