Inhibition of G9a by a small molecule inhibitor, UNC0642, induces apoptosis of human bladder cancer cells

doi:10.1038/s41401-018-0205-5

	Inhibition of G9a by a small molecule inhibitor, UNC0642, induces apoptosis of human bladder cancer cells
	Cao, Yue-peng 1; Sun, Jing-ya 2,3; Li, Mei-qian 4; Dong, Yu 2,5; Zhang, Yuan-heng 2,3; Yan, Jun 4; Huang, Rui-min 2,3; Yan, Xiang 1
刊名	ACTA PHARMACOLOGICA SINICA
	2019-08-01
卷号	40 期号:8 页码:1076-1084
关键词	human urinary bladder cancer G9a UNC0642 apoptosis
ISSN号	1671-4083
DOI	10.1038/s41401-018-0205-5
通讯作者	Yan, Jun(yanjun@nju.edu.cn) ; Huang, Rui-min(rmhuang@simm.ac.cn) ; Yan, Xiang(yanxiang@nju.edu.cn)
英文摘要	Urinary bladder cancer (UBC) is characterized by frequent recurrence and metastasis despite the standard chemotherapy with gemcitabine and cisplatin combination. Histone modifiers are often dysregulated in cancer development, thus they can serve as an excellent drug targets for cancer therapy. Here, we investigated whether G9a, one of the histone H3 methyltransferases, was associated with UBC development. We first analyzed clinical data from public databases and found that G9a was significantly overexpressed in UBC patients. The TCGA Provisional dataset showed that the average expression level of G9a in primary UBC samples (n = 408) was 1.6-fold as much as that in normal bladder samples (n = 19; P < 0.001). Then we used small interfering RNA to knockdown G9a in human UBC T24 and J82 cell lines in vitro, and observed that the cell viability was significantly decreased and cell apoptosis induced. Next, we choosed UNC0642, a small molecule inhibitor targeting G9a, with low cytotoxicity, and excellent in vivo pharmacokinetic properties, to test its anticancer effects against UBC cells in vitro and in vivo. Treatment with UNC0642 dose-dependently decreased the viability of T24, J82, and 5637 cells with the IC50 values of 9.85 +/- 0.41, 13.15 +/- 1.72, and 9.57 +/- 0.37 mu M, respectively. Furthermore, treatment with UNC0642 (1-20 mu M) dose-dependently decreased the levels of histone H3K9me2, the downstream target of G9a, and increased apoptosis in T24 and J82 cells. In nude mice bearing J82 engrafts, administration of UNC0642 (5 mg/kg, every other day, i.p., for 6 times) exerted significant suppressive effect on tumor growth without loss of mouse body weight. Moreover, administration of UNC0642 significantly reduced Ki67 expression and increased the level of cleaved Caspase 3 and BIM protein in J82 xenografts evidenced by immunohistochemistry and western blot analysis, respectively. Taken together, our data demonstrated that G9a may be a promising therapeutic target for UBC, and an epigenetics-based therapy by UNC0642 is suggested.
资助项目	Institutional Technology Service Center of Shanghai Institute of Materia Medica ; National Natural Science Foundation of China[81771890] ; National Natural Science Foundation of China[81772712] ; One Hundred Talent Program of Chinese Academy of Sciences ; China Postdoctoral Science Foundation[2018M630484]
WOS关键词	METHYLATION ; BIX-01294 ; PROLIFERATION ; SURVIVAL ; EHMT2 ; P53
WOS研究方向	Chemistry ; Pharmacology & Pharmacy
语种	英语
出版者	NATURE PUBLISHING GROUP
WOS记录号	WOS:000477938200010
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/289113]
专题	中国科学院上海药物研究所
通讯作者	Yan, Jun; Huang, Rui-min; Yan, Xiang
作者单位	1.Nanjing Univ, Nanjing Drum Tower Hosp, Dept Urol, Sch Med, Nanjing 210008, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China 3.Univ Chinese Acad Sci, Beijing 100049, Peoples R China 4.Nanjing Univ, Model Anim Res Ctr, MOE Key Lab Model Anim Dis Study, Nanjing 210061, Jiangsu, Peoples R China 5.Shanghai Univ, Shanghai 200444, Peoples R China
推荐引用方式 GB/T 7714	Cao, Yue-peng,Sun, Jing-ya,Li, Mei-qian,et al. Inhibition of G9a by a small molecule inhibitor, UNC0642, induces apoptosis of human bladder cancer cells[J]. ACTA PHARMACOLOGICA SINICA,2019,40(8):1076-1084.
APA	Cao, Yue-peng.,Sun, Jing-ya.,Li, Mei-qian.,Dong, Yu.,Zhang, Yuan-heng.,...&Yan, Xiang.(2019).Inhibition of G9a by a small molecule inhibitor, UNC0642, induces apoptosis of human bladder cancer cells.ACTA PHARMACOLOGICA SINICA,40(8),1076-1084.
MLA	Cao, Yue-peng,et al."Inhibition of G9a by a small molecule inhibitor, UNC0642, induces apoptosis of human bladder cancer cells".ACTA PHARMACOLOGICA SINICA 40.8(2019):1076-1084.