Downregulation of TET1 Promotes Bladder Cancer Cell Proliferation and Invasion by Reducing DNA Hydroxymethylation of AJAP1

doi:10.3389/fonc.2020.00667

	Downregulation of TET1 Promotes Bladder Cancer Cell Proliferation and Invasion by Reducing DNA Hydroxymethylation of AJAP1
	Yan, Yi-lin 2; Huang, Zheng-nan 2; Zhu, Zhen 3; Cui, Yang-yan 3; Li, Mei-qian 3; Huang, Rui-min 1,4; Yan, Jun 5; Shen, Bing 2
刊名	FRONTIERS IN ONCOLOGY
	2020-05-21
卷号	10 页码:16
关键词	ten-eleven translocation 1 (TET1) DNA methylation bladder cancer vitamin C adherens junction-associated protein 1 (AJAP1)
ISSN号	2234-943X
DOI	10.3389/fonc.2020.00667
通讯作者	Huang, Rui-min(rmhuang@simm.ac.cn) ; Yan, Jun(yan_jun@fudan.edu.cn) ; Shen, Bing(shenbingyishi@163.com)
英文摘要	Ten-eleven translocation 1 (TET1) is a member of methylcytosine dioxygenase, which catalyzes 5-methylcytosine (5 mC) to 5-hydroxymethylcytosine (5 hmC) to promote the demethylation process. The dysregulated TET1 protein and 5 hmC level were reported to either suppress or promote carcinogenesis in a cancer type-dependent manner. Currently, the role of TET1 in the development of urinary bladder cancer (UBC) and its underlying molecular mechanisms remain unclear. Herein, we found that TET1 expression was downregulated in UBC specimens compared with normal urothelium and was inversely related to tumor stage and grade and overall survival, suggesting its negative association with UBC progression. TET1 silencing in UBC cells increased cell proliferation and invasiveness while the ectopic expression of wild-type TET1-CD, but not its enzymatic inactive mutant, reversed these effects and suppressed tumorigenicity in vivo. In addition, as a direct regulator of TET1 activity, vitamin C treatment increased 5 hmC level and inhibited the anchorage-independent growth and tumorigenicity of UBC cells. Furthermore, we found that TET1 maintained the hypomethylation in the promoter of the AJAP1 gene, which codes for adherens junction-associated protein 1. The downregulation of AJAP1 reversed TET1-CD-induced nuclear translocation of beta-catenin, thus inhibiting the expression of its downstream genes. In human UBC specimens, AJAP1 is frequently downregulated and positively associated with TET1. Notably, low expression levels of both TET1 and AJAP1 predict poor prognosis in UBC patients. In conclusion, we found that the frequently downregulated TET1 level reduces the hydroxymethylation of AJAP1 promoter and subsequently activates beta-catenin signaling to promote UBC development. The downregulation of both TET1 and AJAP1 might be a promising prognostic biomarker for UBC patients.
资助项目	National Natural Science Foundation[81672873] ; National Natural Science Foundation[81872373] ; National Natural Science Foundation[91859106] ; National Science & Technology Major Project Key New Drug Creation and Manufacturing Program, China[2018ZX09711002010-001] ; One Hundred Talent Program of Chinese Academy of Sciences ; Wu Jieping Medical Foundation[320.6750.16051] ; Shanghai Songjiang Municipal Science and Technology Commission Natural Science Foundation[17SJKJGG10] ; Shanghai Specialized Research Fund for Integrated Chinese and Western Medicine in General Hospitals[ZHYY-ZXYJHZX-1-201705]
WOS关键词	TUMOR-SUPPRESSOR ; METHYLATION ; PATHWAY ; 5-HYDROXYMETHYLCYTOSINE ; EXPRESSION ; RESISTANCE ; INHIBITORS ; EXERTS
WOS研究方向	Oncology
语种	英语
出版者	FRONTIERS MEDIA SA
WOS记录号	WOS:000539402500001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/291730]
专题	中国科学院上海药物研究所
通讯作者	Huang, Rui-min; Yan, Jun; Shen, Bing
作者单位	1.Univ Chinese Acad Sci, Beijing, Peoples R China 2.Shanghai Jiao Tong Univ, Shanghai Gen Hosp, Dept Urol, Sch Med, Shanghai, Peoples R China 3.Nanjing Univ, Model Anim Res Ctr, Nanjing, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai, Peoples R China 5.Fudan Univ, Dept Lab Anim Sci, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Yan, Yi-lin,Huang, Zheng-nan,Zhu, Zhen,et al. Downregulation of TET1 Promotes Bladder Cancer Cell Proliferation and Invasion by Reducing DNA Hydroxymethylation of AJAP1[J]. FRONTIERS IN ONCOLOGY,2020,10:16.
APA	Yan, Yi-lin.,Huang, Zheng-nan.,Zhu, Zhen.,Cui, Yang-yan.,Li, Mei-qian.,...&Shen, Bing.(2020).Downregulation of TET1 Promotes Bladder Cancer Cell Proliferation and Invasion by Reducing DNA Hydroxymethylation of AJAP1.FRONTIERS IN ONCOLOGY,10,16.
MLA	Yan, Yi-lin,et al."Downregulation of TET1 Promotes Bladder Cancer Cell Proliferation and Invasion by Reducing DNA Hydroxymethylation of AJAP1".FRONTIERS IN ONCOLOGY 10(2020):16.