Endogenous authentic OCT4A proteins directly regulate FOS/AP-1 transcription in somatic cancer cells.
Endogenous authentic OCT4A proteins directly regulate FOS/AP-1 transcription in somatic cancer cells.
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内源性真实 OCT4A 蛋白直接调节体癌细胞中的 FOS/AP-1 转录
DOI：
10.1038/s41419-018-0606-x
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发表时间：
2018-05-22
影响因子：
9
通讯作者：
Wang YJ
中科院分区：
文献类型：
--
作者：
Zhou Y;Chen X;Kang B;She S;Zhang X;Chen C;Li W;Chen W;Dan S;Pan X;Liu X;He J;Zhao Q;Zhu C;Peng L;Wang H;Yao H;Cao H;Li L;Herlyn M;Wang YJ
OCT4A被公认为多能干细胞（PSC）自我更新的主要转录因子和启动体细胞重编程的先锋因子，但其在体细胞癌细胞中的存在和功能仍然存在争议和模糊。通过将基于CRISPR-Cas9的基因编辑与高特异性PCR测定、高灵敏度免疫测定和质谱法相结合，我们在此提供了明确的证据，证明全长真实的OCT4A转录物和蛋白质都存在于体细胞癌细胞中，并且OCT4A蛋白质在整个细胞群中异质表达，并且当表达时，它们主要位于细胞核中。尽管它们的丰度极低（比PSC低大约三个数量级），但OCT4A蛋白与AP-1转录因子亚基c-FOS基因的启动子/增强子区域结合，并严格调节其转录。敲除体细胞癌细胞中的OCT4A导致c-FOS蛋白水平显著降低、异常AP-1信号传导、抑制自我更新能力、与体外和体内细胞生长迟缓相关的细胞迁移缺陷以及它们对抗癌药物的敏感性增强。总之，我们解决了该领域长期存在的争议和不确定性，并揭示了OCT4A蛋白在调节FOS/AP-1信号中心基因中的基本作用，这些基因介导了体细胞癌细胞的粘附，迁移和繁殖。
OCT4A is well established as a master transcription factor for pluripotent stem cell (PSC) self-renewal and a pioneer factor for initiating somatic cell reprogramming, yet its presence and functionality in somatic cancer cells remain controversial and obscure. By combining the CRISPR-Cas9-based gene editing with highly specific PCR assays, highly sensitive immunoassays, and mass spectrometry, we provide unequivocal evidence here that full-length authentic OCT4A transcripts and proteins were both present in somatic cancer cells, and OCT4A proteins were heterogeneously expressed in the whole cell population and when expressed, they are predominantly localized in cell nucleus. Despite their extremely low abundance (approximately three orders of magnitude lower than in PSCs), OCT4A proteins bound to the promoter/enhancer regions of the AP-1 transcription factor subunit c-FOS gene and critically regulated its transcription. Knocking out OCT4A in somatic cancer cells led to dramatic reduction of the c-FOS protein level, aberrant AP-1 signaling, dampened self-renewal capacity, deficient cell migration that were associated with cell growth retardation in vitro and in vivo, and their enhanced sensitivity to anticancer drugs. Taken together, we resolve the long-standing controversy and uncertainty in the field, and reveal a fundamental role of OCT4A protein in regulating FOS/AP-1 signaling-centered genes that mediate the adhesion, migration, and propagation of somatic cancer cells.
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影响因子：
16
作者：
Lin, Yuanji;Yang, Ying;Li, Weihua;Chen, Qi;Li, Jie;Pan, Xiao;Zhou, Lina;Liu, Changwei;Chen, Chunsong;He, Jianqin;Cao, Hongcui;Yao, Hangping;Zheng, Li;Xu, Xiaowei;Xia, Zongping;Ren, Jiangtao;Xiao, Lei;Li, Lanjuan;Shen, Binghui;Zhou, Honglin;Wang, Ying-Jie
通讯作者：
Wang, Ying-Jie
色氨酸衍生物调节干细胞样癌细胞中 Oct4 的转录。
影响因子：
16.6
作者：
Cheng, Jie;Li, Wenxin;Kang, Bo;Zhou, Yanwen;Song, Jiasheng;Dan, Songsong;Yang, Ying;Zhang, Xiaoqian;Li, Jingchao;Yin, Shengyong;Cao, Hongcui;Yao, Hangping;Zhu, Chenggang;Yi, Wen;Zhao, Qingwei;Xu, Xiaowei;Zheng, Min;Zheng, Shusen;Li, Lanjuan;Shen, Binghui;Wang, Ying-Jie
通讯作者：
Wang, Ying-Jie
影响因子：
5.2
作者：
Babaie, Yasmin;Herwig, Ralf;Adjaye, James
通讯作者：
Adjaye, James
影响因子：
2.9
作者：
Linning, KD;Tai, MH;Olson, LK
通讯作者：
Olson, LK
影响因子：
11.5
作者：
Chang, Te-Sheng;Wu, Yu-Chih;Huang, Yen-Hua
通讯作者：
Huang, Yen-Hua