Epigenetic inactivation of the candidate tumor suppressor gene ASC/TMS1 in human renal cell carcinoma and its role as a potential therapeutic target.
Epigenetic inactivation of the candidate tumor suppressor gene ASC/TMS1 in human renal cell carcinoma and its role as a potential therapeutic target.
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人肾细胞癌候选抑癌基因ASC/TMS1的表观遗传失活及其作为潜在治疗靶点的作用
DOI：
10.18632/oncotarget.4256
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发表时间：
2015-09-08
期刊：
影响因子：
--
通讯作者：
Zhang Q
中科院分区：
文献类型：
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作者：
Liu Q;Jin J;Ying J;Cui Y;Sun M;Zhang L;Fan Y;Xu B;Zhang Q
本研究探讨促凋亡基因ASC/TM 1在肾癌中的表观遗传学改变及其生物学功能。在6个肾癌细胞系中，有5个细胞ASC/TM 1表达下调。与邻近的非癌组织相比，在67对肾肿瘤中也检测到显著的下调。ASC/TM 1基因表达下调与启动子高甲基化有关，经去甲基化处理后可恢复。ASC/TM 1在沉默的肾癌细胞系中的重新表达抑制了SCID小鼠的细胞活力、集落形成、细胞周期停滞、细胞凋亡、细胞侵袭和成瘤性。ASC/TM 1在肾癌中的抗肿瘤作用部分是通过激活p53和p21信号来调节的。此外，ASC/TM 1的修复增加了肾细胞对DNA损伤剂的敏感性。ASC/TM 1基因敲除可减少DNA损伤剂诱导的P53活化和细胞凋亡。此外，41.1%(83/202)的肾癌组织中还检测到ASC/TM_1高甲基化，而癌旁组织中仅有12%检测到ASC/TM_1高甲基化。ASC/TM 1甲基化与较高的肿瘤核分级显著相关。综上所述，ASC/TM 1在肾癌发生中是一种新的功能性肿瘤抑制因子。ASC/TM 1肿瘤特异性甲基化可能是设计改进的肾癌诊断和治疗策略的有用生物标志物。
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.