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TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs

Abstract

Aberrant expression of microRNAs (miRNAs) and the enzymes that control their processing have been reported in multiple biological processes including primary and metastatic tumours1,2,3,4,5,6, but the mechanisms governing this are not clearly understood. Here we show that TAp63, a p53 family member, suppresses tumorigenesis and metastasis, and coordinately regulates Dicer and miR-130b to suppress metastasis. Metastatic mouse and human tumours deficient in TAp63 express Dicer at very low levels, and we found that modulation of expression of Dicer and miR-130b markedly affected the metastatic potential of cells lacking TAp63. TAp63 binds to and transactivates the Dicer promoter, demonstrating direct transcriptional regulation of Dicer by TAp63. These data provide a novel understanding of the roles of TAp63 in tumour and metastasis suppression through the coordinate transcriptional regulation of Dicer and miR-130b and may have implications for the many processes regulated by miRNAs.

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Figure 1: TAp63 −/− mice develop metastatic tumours.
Figure 2: TAp63 -deficient tumours show high levels of senescence and genomic instability.
Figure 3: TAp63 regulates metastasis by transcriptional activation of Dicer.
Figure 4: TAp63 regulates miR-130b in metastasis.

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Acknowledgements

We thank C.-g. Liu for technical assistance with miRNA analyses and A. Multani for metaphase analyses (funded by NCI CA16672); K. Y. Tsai for scientific discussions and comments on the manuscript; and D. Yu, J. Jackson and S. Rehman for reagents and advice. This work was supported by grants to E.R.F. from the American Cancer Society (RSG-07-082-01-MGO), the Susan G. Komen Foundation (BCTR600208) and the Hildegardo E. and Olga M. Flores Foundation. This work was supported in part by an NCI-Cancer Center Core Grant (CA-16672) (University of Texas M. D. Anderson Cancer Center), a Career Development Award from the Genitourinary Cancer SPORE (P50CA091846) to E.R.F., Lung Cancer SPORE (P50CA070907) to I.W. and U01DE019765 to A.E.-N. E.R.F. is a scholar of the Rita Allen Foundation and the V Foundation for Cancer Research.

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Authors

Contributions

X.S., D.C. and E.R.F. designed the experiments and analysed the data. X.S., D.C., M.S.C., L.L., Y.J.G., Y.-L.L. and M.L.L. performed the experiments. A.E.-N. performed pathology analysis and provided human HNSCC samples. M.B.S. and I.W. provided human lung adenocarcinoma pathology information and RNA samples. C.J.C. performed statistical analysis on miRNA data. X.S., D.C. and E.R.F. wrote the manuscript. All authors discussed the results and commented on the manuscript.

Corresponding author

Correspondence to Elsa R. Flores.

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The authors declare no competing financial interests.

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Su, X., Chakravarti, D., Cho, M. et al. TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs. Nature 467, 986–990 (2010). https://doi.org/10.1038/nature09459

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