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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-449 a/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.

genes and development

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