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TAp63 suppresses metastasis through coordinate regulation of Dicer and miRNAs

26 May 2023 Editor’s Note: Readers are alerted that the reliability of data presented in this manuscript is currently in question. Appropriate editorial action will be taken once this matter is resolved.

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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  • 26 May 2023

    Editor’s Note: Readers are alerted that the reliability of data presented in this manuscript is currently in question. Appropriate editorial action will be taken once this matter is resolved.

References

  1. Baffa, R. et al. MicroRNA expression profiling of human metastatic cancers identifies cancer gene targets. J. Pathol.219, 214–221 (2009)

    Article  CAS  PubMed  Google Scholar 

  2. Gibbons, D. L. et al. Contextual extracellular cues promote tumor cell EMT and metastasis by regulating miR-200 family expression. Genes Dev.23, 2140–2151 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Ma, L., Teruya-Feldstein, J. & Weinberg, R. A. Tumour invasion and metastasis initiated by microRNA-10b in breast cancer. Nature449, 682–628 (2007)

    Article  ADS  CAS  PubMed  Google Scholar 

  4. Kumar, M. S. et al. Dicer1 functions as a haploinsufficient tumor suppressor. Genes Dev.23, 2700–2704 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Lu, J. et al. MicroRNA expression profiles classify human cancers. Nature435, 834–8 (2005)

    Article  ADS  CAS  PubMed  Google Scholar 

  6. Merritt, W. M. et al. Dicer, Drosha, and outcomes in patients with ovarian cancer. N. Engl. J. Med.359, 2641–2650 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Flores, E. R. The roles of p63 in cancer. Cell Cycle6, 300–304 (2007)

    Article  CAS  PubMed  Google Scholar 

  8. Flores, E. R. et al. Tumor predisposition in mice mutant for p63 and p73: evidence for broader tumor suppressor functions for the p53 family. Cancer Cell7, 363–373 (2005)

    Article  CAS  PubMed  Google Scholar 

  9. Keyes, W. M. et al. p63 heterozygous mutant mice are not prone to spontaneous or chemically induced tumors. Proc. Natl Acad. Sci. USA103, 8435–8440 (2006)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  10. Yang, A., Kaghad, M., Caput, D. & McKeon, F. On the shoulders of giants: p63, p73 and the rise of p53. Trends Genet.18, 90–95 (2002)

    Article  PubMed  Google Scholar 

  11. Hibi, K. et al. AIS is an oncogene amplified in squamous cell carcinoma. Proc. Natl Acad. Sci. USA97, 5462–5467 (2000)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  12. Park, B. J. et al. Frequent alteration of p63 expression in human primary bladder carcinomas. Cancer Res.60, 3370–3374 (2000)

    CAS  PubMed  Google Scholar 

  13. Urist, M. J. et al. Loss of p63 expression is associated with tumor progression in bladder cancer. Am. J. Pathol.161, 1199–1206 (2002)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Park, H. R. et al. Low expression of p63 and p73 in osteosarcoma. Tumori90, 239–243 (2004)

    Article  CAS  PubMed  Google Scholar 

  15. Yang, A. et al. p63, a p53 homolog at 3q27–29, encodes multiple products with transactivating, death-inducing, and dominant-negative activities. Mol. Cell2, 305–316 (1998)

    Article  CAS  PubMed  Google Scholar 

  16. Jacks, T. et al. Tumor spectrum analysis in p53-mutant mice. Curr. Biol.4, 1–7 (1994)

    Article  CAS  PubMed  Google Scholar 

  17. Lang, G. A. et al. Gain of function of a p53 hot spot mutation in a mouse model of Li–Fraumeni syndrome. Cell119, 861–872 (2004)

    Article  CAS  PubMed  Google Scholar 

  18. Olive, K. P. et al. Mutant p53 gain of function in two mouse models of Li–Fraumeni syndrome. Cell119, 847–860 (2004)

    Article  CAS  PubMed  Google Scholar 

  19. Su, X. et al. TAp63 prevents premature aging by promoting adult stem cell maintenance. Cell Stem Cell5, 64–75 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Maruya, S. et al. Differential methylation status of tumor-associated genes in head and neck squamous carcinoma: incidence and potential implications. Clin. Cancer Res.10, 3825–3830 (2004)

    Article  CAS  PubMed  Google Scholar 

  21. Jackson, E. L. et al. Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-ras. Genes Dev.15, 3243–3248 (2001)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Kumar, M. S. et al. Impaired microRNA processing enhances cellular transformation and tumorigenesis. Nature Genet.39, 673–677 (2007)

    Article  CAS  PubMed  Google Scholar 

  23. He, L. et al. A microRNA component of the p53 tumour suppressor network. Nature447, 1130–1134 (2007)

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  24. Flores, E. R. et al. p63 and p73 are required for p53-dependent apoptosis in response to DNA damage. Nature416, 560–564 (2002)

    Article  ADS  CAS  PubMed  Google Scholar 

  25. Pruneri, G. et al. The transactivating isoforms of p63 are overexpressed in high-grade follicular lymphomas independent of the occurrence of p63 gene amplification. J. Pathol.206, 337–345 (2005)

    Article  CAS  PubMed  Google Scholar 

  26. Mudhasani, R. et al. Loss of miRNA biogenesis induces p19Arf-p53 signaling and senescence in primary cells. J. Cell Biol.181, 1055–1063 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Su, X. et al. Rescue of key features of the p63-null epithelial phenotype by inactivation of Ink4a and Arf . EMBO J.28, 1904–1915 (2009)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Landthaler, M. et al. Molecular characterization of human Argonaute-containing ribonucleoprotein complexes and their bound target mRNAs. RNA14, 2580–2596 (2008)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Lin, Y. L. et al. p63 and p73 transcriptionally regulate genes involved in DNA repair. PLoS Genet.5, e1000680 (2009)

    Article  PubMed  PubMed Central  Google Scholar 

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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.

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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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