A positive feedback between p53 and miR-34 miRNAs mediates tumor suppression
- Nobuhiro Okada1,
- Chao-Po Lin1,
- Marcelo C. Ribeiro1,
- Anne Biton2,
- Gregory Lai1,
- Xingyue He3,
- Pengcheng Bu1,
- Hannes Vogel4,
- David M. Jablons5,
- Andreas C. Keller6,7,
- J. Erby Wilkinson8,
- Biao He5,
- Terry P. Speed2 and
- Lin He1,9
- 1Molecular and Cell Biology Department, University of California at Berkeley, Berkeley, California 94705, USA;
- 2Department of Statistics, University of California at Berkeley, Berkeley, California 94705, USA;
- 3Takeda Oncology Company, Cambridge, Massachusetts 02139, USA;
- 4Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA;
- 5Thoracic Oncology Program, Department of Surgery, University of California at San Francisco, San Francisco, California 94115, USA;
- 6Department of Clinical Bioinformatics, Saarland University, University Hospital, 66041 Saarbücken, Germany;
- 7Technology Innovation, Siemens Healthcare, 91052 Erlangen, Germany;
- 8Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA
Abstract
As bona fide p53 transcriptional targets, miR-34 microRNAs (miRNAs) exhibit frequent alterations in many human tumor types and elicit multiple p53 downstream effects upon overexpression. Unexpectedly, miR-34 deletion alone fails to impair multiple p53-mediated tumor suppressor effects in mice, possibly due to the considerable redundancy in the p53 pathway. Here, we demonstrate that miR-34a represses HDM4, a potent negative regulator of p53, creating a positive feedback loop acting on p53. In a Kras-induced mouse lung cancer model, miR-34a deficiency alone does not exhibit a strong oncogenic effect. However, miR-34a deficiency strongly promotes tumorigenesis when p53 is haploinsufficient, suggesting that the defective p53–miR-34 feedback loop can enhance oncogenesis in a specific context. The importance of the p53/miR-34/HDM4 feedback loop is further confirmed by an inverse correlation between miR-34 and full-length HDM4 in human lung adenocarcinomas. In addition, human lung adenocarcinomas generate an elevated level of a short HDM4 isoform through alternative polyadenylation. This short HDM4 isoform lacks miR-34-binding sites in the 3′ untranslated region (UTR), thereby evading miR-34 regulation to disable the p53-miR-34 positive feedback. Taken together, our results elucidated the intricate cross-talk between p53 and miR-34 miRNAs and revealed an important tumor suppressor effect generated by this positive feedback loop.
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Footnotes
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↵9 Corresponding author
E-mail lhe{at}berkeley.edu
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.233585.113.
- Received October 25, 2013.
- Accepted January 15, 2014.
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