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ZY0511, a novel, potent and selective LSD1 inhibitor, exhibits anticancer activity against solid tumors via the DDIT4/mTOR pathway.

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资源类型：
Pubmed体系：
作者：
Li Yan[1] * ; Tao Lei[1] * ; Zuo Zeping[1] * ; Zhou Yang[2] ; Qian Xinying[1] ; Lin Yiyun[1] ; Jie Hui[1] ; Liu Chunqi[1] ; Li Zhuoling[1] ; Zhang Huaqin[1] ; Zhang Hu[3] ; Cen Xiaobo[4] ; Yang Shengyong[1,*2] ; Zhao Yinglan[1,*1] ;
机构： [1]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, and Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, 610041, China [2]Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu, 610041, China [3]Department of Gastroenterology, West China Hospital, West China Medical School, Sichuan University, Chengdu, 610041, China [4]National Chengdu Center for Safety Evaluation of Drugs, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Collaborative Innovation Center for Biotherapy, Chengdu, 610041, China
出处：
DOI： 10.1016/j.canlet.2019.03.052
ISSN：

关键词： Colorectal cancer Cervical cancer H3K4 methylation Chemotherapy sensitivity

摘要：
Lysine-specific demethylase1 (LSD1) plays a crucial role in cancer and has become a promising target for cancer therapy. However, the mechanism underlying the role of LSD1 in oncogenesis is poorly understood, and more effective LSD1 inhibitors are needed. Here we report the biological activity of a novel LSD1 inhibitor named ZY0511. ZY0511 specifically inhibited LSD1 activity and the proliferation of various human cancer cells especially the HeLa and HCT116 cells. ZY0511 significantly increased the expression of DDIT4, a known mTORC1 suppressor, which was a direct downstream target of LSD1 confirmed by ChIP-PCR. ZY0511-induced LSD1 inhibition upregulated the expression of DDIT4 by altering histone H3K4 methylation levels at its promoter, thus suppressing mTORC1 activity. Knockdown of DDIT4 attenuated the anticancer effect of ZY0511. Intraperitoneal administration of ZY0511 significantly prevented the growth of HCT116 and HeLa xenografts in mice and showed no detectable toxicity. Moreover, DDIT4 expression was correlated with the sensitivity of human cancer cells to chemotherapy. Taken together, ZY0511 showed therapeutic potential for solid tumors, the induction of DDIT4 may be used as a predictive biomarker of LSD1 inhibitors. Copyright © 2019 Elsevier B.V. All rights reserved.

基金：
National Natural Science Foundation of China (81773198), National Keypoint Research and Invention Program of the China Ministry of Science and Technology (MOST-2016YFC1303200) and National S&T Major project (2018ZX09201018).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2019]版：
大类 | 2 区 医学
小类 | 2 区 肿瘤学
最新[2023]版：
大类 | 1 区 医学
小类 | 2 区 肿瘤学
第一作者：
第一作者机构： [1]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, and Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, 610041, China
共同第一作者：
通讯作者：
通讯机构： [1]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, and Collaborative Innovation Center for Biotherapy, Sichuan University, Chengdu, 610041, China [*1]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, #17, 3rd Section, Ren min South Road, Chengdu, 610041, China. [*2]State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, West China Medical School, Sichuan University, #17, 3rd Section, Ren min South Road, Chengdu, 610041, China.
推荐引用方式(GB/T 7714)：
Li Yan,Tao Lei,Zuo Zeping,et al.ZY0511, a novel, potent and selective LSD1 inhibitor, exhibits anticancer activity against solid tumors via the DDIT4/mTOR pathway.[J].Cancer letters.2019,454:179-190.doi:10.1016/j.canlet.2019.03.052.
APA：
Li Yan,Tao Lei,Zuo Zeping,Zhou Yang,Qian Xinying...&Zhao Yinglan.(2019).ZY0511, a novel, potent and selective LSD1 inhibitor, exhibits anticancer activity against solid tumors via the DDIT4/mTOR pathway..Cancer letters,454,
MLA：
Li Yan,et al."ZY0511, a novel, potent and selective LSD1 inhibitor, exhibits anticancer activity against solid tumors via the DDIT4/mTOR pathway.".Cancer letters 454.(2019):179-190

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