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

Abstract

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, miR449a/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.Supplemental material is available at http://www.genesdev.org.

MicroRNA therapy inhibits hepatoblastoma growth in vivo by targeting β‐catenin and Wnt signaling

“…While such ability has been described for miR‐449b‐5p and let‐7i‐5p,35, 36 this is the first description of an antitumoral function for their miRNA “3p” counterparts and for miR‐624‐5p and miR‐885‐5p. By comparing the data in Figs.…”

Macro-management of microRNAs in cell cycle progression of tumor cells and its implications in anti-cancer therapy

“…One example is cyclin D1, which is regulated by miR449a [35] , miR-193b [36] , miR-15/16 [37][38][39] , miR-19a [40] , miR-195 [41] , and miR-302a [42] . The cyclin D1 binding proteins CDK4 and CDK6 are also regulated by a number of miRNAs, including miR-107 [43] , miR-449a [44] , miR-129 [45] , miR-125b [46] , miR-15/16 [39] , miR-24 [47] , miR-195 [41] , and miR-124a [48] . Another important G 1 /S regulator cyclin E, is down-regulated by miR-16 [37] and miR-195 [49] .…”

E2F1-inducible microRNA 449a/b suppresses cell proliferation and promotes apoptosis

“…[15][16][17][18][19][20] These findings raise the question whether E2F1 may also induce miRNAs that contribute to apoptosis. Indeed, E2F1-responsive miRNAs were previously 21,22 identified and at least partially characterized according to their role in cancer, but mostly with antiapoptotic functions [23][24][25] or with no reported influence on apoptosis. To identify a more complete set of E2F1-inducible miRNAs, we performed array hybridization and found miR-449a and miR-449b (collectively termed miR-449 from here on) to be strongly E2F1-responsive, in agreement with a recent report.…”

“…To identify a more complete set of E2F1-inducible miRNAs, we performed array hybridization and found miR-449a and miR-449b (collectively termed miR-449 from here on) to be strongly E2F1-responsive, in agreement with a recent report. 22 Strikingly, miR-449 shares seed sequences and target genes with the miR-34 family. miR-449 potently induces apoptosis and also upregulates p53 activity.…”