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.
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.
Yang
Xiaojing
X
Cancer Biology and Pharmacology, Genome Institute of Singapore, A*STAR (Agency for Science, Technology, and Research), Singapore 138672.
Feng
Min
M
Jiang
Xia
X
Wu
Zhenlong
Z
Li
Zhimei
Z
Aau
Meiyee
M
Yu
Qiang
Q
D002460:Cell Line; D045744:Cell Line, Tumor; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D050687:E2F1 Transcription Factor / Q000378:metabolism*; D044127:Epigenesis, Genetic; D025461:Feedback, Physiological / Q000235:genetics*; D016193:G1 Phase / Q000502:physiology; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D009369:Neoplasms / Q000503:physiopathology; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism*
D050687:E2F1 Transcription Factor; D006657:Histones; C544530:MIRN449 microRNA, human; D035683:MicroRNAs; D051361:Cyclin-Dependent Kinase 6; D020687:cdc25 Phosphatases