miR-449a and miR-449b are direct transcriptional targets of E2F1 and negatively regulate pRb-E2F1 activity through a feedback loop by targeting CDK6 and CDC25A

被引:203
作者
Yang, Xiaojing [1 ]
Feng, Min [1 ]
Jiang, Xia [1 ]
Wu, Zhenlong [1 ]
Li, Zhimei [1 ]
Aau, Meiyee [1 ]
Yu, Qiang [1 ,2 ]
机构
[1] ASTAR, Genome Inst Singapore, Singapore 138672, Singapore
[2] Natl Univ Singapore, Dept Physiol, Yong Loo Lin Sch Med, Singapore 117597, Singapore
关键词
CDC25A; CDK6; DZNep; E2F1; miR-449; HISTONE H3; EXPRESSION; MICRORNAS; CANCER; METHYLATION; SIGNATURE; GENES; PLURIPOTENT; PHOSPHATASE; ACTIVATION;
D O I
10.1101/gad.1819009
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
The Rb-E2F pathway drives cell cycle progression and cell proliferation, and the molecular strategies safeguarding its activity are not fully understood. Here we report that E2F1 directly transactivates miR-449a/b. miR-449a/b targets and inhibits oncogenic CDK6 and CDC25A, resulting in pRb dephosphorylation and cell cycle arrest at G1 phase, revealing a negative feedback regulation of the pRb-E2F1 pathway. Moreover, miR-449a/b expression in cancer cells is epigenetically repressed through histone H3 Lys27 trimethylation, and epigenetic drug treatment targeting histone methylation results in strong induction of miR-449a/b. Our study reveals a tumor suppressor function of miR-449a/b through regulating Rb/E2F1 activity, and suggests that escape from this regulation through an aberrant epigenetic event contributes to E2F1 deregulation and unrestricted proliferation in human cancer.
引用
收藏
页码:2388 / 2393
页数:6
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