inhibitionofg9abyasmallmoleculeinhibitorunc0642inducesapoptosisofhumanbladdercancercells

doi:10.1038/s41401-018-0205-5

	inhibitionofg9abyasmallmoleculeinhibitorunc0642inducesapoptosisofhumanbladdercancercells
	Cao Yuepeng 2; Sun Jingya 3; Li Meiqian 1; Dong Yu 3; Zhang Yuanheng 3; Yan Jun 1; Huang Ruimin 3; Yan Xiang 2
刊名	actapharmacologicasinica
	2019
卷号	40 期号:8 页码:1076
关键词	METHYLATION BIX-01294 PROLIFERATION SURVIVAL EHMT2 P53 human urinary bladder cancer G9a UNC0642 apoptosis
ISSN号	1671-4083
DOI	10.1038/s41401-018-0205-5
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] ; [One Hundred Talent Program of Chinese Academy of Sciences] ; [China Postdoctoral Science Foundation]
语种	英语
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/286519]
专题	中国科学院上海药物研究所
作者单位	1.南京大学 2.Department of Urology,Nanjing Drum Tower Hospital,Nanjing University Medical School 3.中国科学院上海药物研究所
推荐引用方式 GB/T 7714	Cao Yuepeng,Sun Jingya,Li Meiqian,et al. inhibitionofg9abyasmallmoleculeinhibitorunc0642inducesapoptosisofhumanbladdercancercells[J]. actapharmacologicasinica,2019,40(8):1076.
APA	Cao Yuepeng.,Sun Jingya.,Li Meiqian.,Dong Yu.,Zhang Yuanheng.,...&Yan Xiang.(2019).inhibitionofg9abyasmallmoleculeinhibitorunc0642inducesapoptosisofhumanbladdercancercells.actapharmacologicasinica,40(8),1076.
MLA	Cao Yuepeng,et al."inhibitionofg9abyasmallmoleculeinhibitorunc0642inducesapoptosisofhumanbladdercancercells".actapharmacologicasinica 40.8(2019):1076.