p53-Suppressed Oncogene TET1 Prevents Cellular Aging in Lung Cancer
p53-Suppressed Oncogene TET1 Prevents Cellular Aging in Lung Cancer
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DOI：
10.1158/0008-5472.can-18-1234
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发表时间：
2019-04-15
期刊：
影响因子：
11.2
通讯作者：
Belinsky, Steven A.
中科院分区：
文献类型：
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作者：
Filipczak, Piotr T.;Leng, Shuguang;Belinsky, Steven A.
转录调节因子10 - 11易位甲基胞嘧啶双加氧酶1（TET 1）在肺癌中的作用尚未得到很好的表征。我们发现TET 1在腺癌和鳞状细胞癌中过表达。TET 1敲低降低了体外和体内细胞生长，并诱导转录组重编程，而不依赖于其去甲基化活性，从而影响关键的癌症信号通路。野生型p53结合TET 1启动子抑制转录，而p53颠换突变与TET 1高表达最密切相关。在p53突变细胞系中TET 1的敲低通过一个程序诱导衰老，该程序涉及表现为DNA单链和双链断裂的广义基因组不稳定性以及与顺铂和阿霉素协同的p21的诱导。这些数据确定TET 1作为肺癌中的癌基因，其通过p53的丧失获得功能可能通过靶向治疗诱导的衰老而被利用。意义：这些研究确定TET 1作为肺癌中的癌基因，其在p53的丧失之后获得功能可能通过靶向治疗诱导的衰老而被利用。
The role of transcriptional regulator ten-eleven translocation methylcytosine dioxygenease 1 (TET1) has not been well characterized in lung cancer. Here we show that TET1 is overexpressed in adenocarcinoma and squamous cell carcinomas. TET1 knockdown reduced cell growth in vitro and in vivo and induced transcriptome reprogramming independent of its demethylating activity to affect key cancer signaling pathways. Wild-type p53 bound the TET1 promoter to suppress transcription, while p53 transversion mutations were most strongly associated with high TET1 expression. Knockdown of TET1 in p53-mutant cell lines induced senescence through a program involving generalized genomic instability manifested by DNA single-and double-strand breaks and induction of p21 that was synergistic with cisplatin and doxorubicin. These data identify TET1 as an oncogene in lung cancer whose gain of function via loss of p53 may be exploited through targeted therapy-induced senescence.Significance: These studies identify TET1 as an oncogene in lung cancer whose gain of function following loss of p53 may be exploited by targeted therapy-induced senescence.