Epigenetic inactivation of the candidate tumor suppressor gene ASC/TMS1 in human renal cell carcinoma and its role as a potential therapeutic target

被引：27
作者：
Liu, Qianling [1 ,2 ]
Jin, Jie [1 ,2 ]
Ying, Jianming [3 ,4 ]
Cui, Yun [1 ,2 ]
Sun, Mengkui [1 ,2 ]
Zhang, Lian [1 ,2 ]
Fan, Yu [1 ,2 ]
Xu, Ben [1 ,2 ]
Zhang, Qian [1 ,2 ]
机构：
[1] Peking Univ, Dept Urol, Hosp 1, Beijing 100034, Peoples R China
[2] Natl Res Ctr Genitourinary Oncol, Inst Urol, Beijing 100034, Peoples R China
[3] Chinese Acad Med Sci, Dept Pathol, Inst Canc, Beijing 100021, Peoples R China
[4] Chinese Acad Med Sci, Canc Hosp, Peking Union Med Coll PUMC, Beijing 100021, Peoples R China
来源：
ONCOTARGET | 2015年 / 6卷 / 26期
关键词：
ASC/TMS1; tumor suppressor; DNA methylation; renal cell carcinoma; chemosensitivity; CASPASE RECRUITMENT DOMAIN; BREAST-CANCER CELLS; NF-KAPPA-B; COLORECTAL-CANCER; DOWN-REGULATION; CLEAR-CELL; P53; APOPTOSIS; ASC; METHYLATION;
D O I：
10.18632/oncotarget.4256
中图分类号：
R73 [肿瘤学];
学科分类号：
100214 ;
摘要：
This study investigated the epigenetic alteration and biological function of the pro-apoptotic gene ASC/TMS1 in renal cell carcinoma. ASC/TMS1 was downregulated in five out of six RCC cell lines. A significant downregulation was also detected in sixty-seven paired renal tumors compared with adjacent non-cancerous tissues. The downregulation of ASC/TMS1 was correlated with promoter hypermethylation and could be restored with demethylation treatment. Re-expression of ASC/TMS1 in silenced RCC cell lines inhibited cell viability, colony formation, arrested cell cycle, induced apoptosis, suppressed cell invasion and repressed tumorigenicity in SCID mice. The antitumorigenic function of ASC/TMS1 in renal cancer was partially regulated by activation of p53 and p21 signaling. In addition, restoration of ASC/TMS1 sensitizes RCC cells to DNA damaging agents. Knockdown of ASC/TMS1 reduced DNA damaging agents-induced p53 activation and cell apoptosis. Moreover, ASC/TMS1 hypermethylation was further detected in 41.1% (83/202) of RCC tumors, but only 12% in adjacent non-cancerous tissues. ASC/TMS1 methylation was significantly correlated with higher tumor nuclear grade. In conclusion, ASC/TMS1 is a novel functional tumor suppressor in renal carcinogenesis. ASC/TMS1 tumor specific methylation may be a useful biomarker for designing improved diagnostic and therapeutic strategies for RCC.
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收藏
页码：22706 / 22723
页数：18
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