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Ras and TGF-beta signaling enhance cancer progression by promoting the Delta Np63 transcriptional program
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab.
Univ Tokyo, Grad Sch Med, Dept Mol Pathol, Bunkyo Ku, Tokyo 1130033, Japan..
Univ Tokyo, Grad Sch Med, Dept Mol Pathol, Bunkyo Ku, Tokyo 1130033, Japan..
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2016 (English)In: Science Signaling, ISSN 1945-0877, E-ISSN 1937-9145, Vol. 9, no 442, ra84Article in journal (Refereed) Published
Abstract [en]

The p53 family of transcription factors includes p63, which is a master regulator of gene expression in epithelial cells. Determining whether p63 is tumor-suppressive or tumorigenic is complicated by isoform-specific and cellular context-dependent protein associations, as well as antagonism from mutant p53. Delta Np63 is an amino-terminal-truncated isoform, that is, the predominant isoform expressed in cancer cells of epithelial origin. In HaCaT keratinocytes, which have mutant p53 and Delta Np63, we found that mutant p53 antagonized Delta Np63 transcriptional activity but that activation of Ras or transforming growth factor-beta (TGF-beta) signaling pathways reduced the abundance of mutant p53 and strengthened target gene binding and activity of Delta Np63. Among the products of Delta Np63-induced genes was dual-specificity phosphatase 6 (DUSP6), which promoted the degradation of mutant p53, likely by dephosphorylating p53. Knocking down all forms of p63 or DUSP6 and DUSP7 (DUSP6/7) inhibited the basal or TGF-beta-induced or epidermal growth factor (which activates Ras)-induced migration and invasion in cultures of p53-mutant breast cancer and squamous skin cancer cells. Alternatively, overexpressing Delta Np63 in the breast cancer cells increased their capacity to colonize various tissues upon intracardiac injection in mice, and this was inhibited by knocking down DUSP6/7 in these Delta Np63-overexpressing cells. High abundance of Delta Np63 in various tumors correlated with poor prognosis in patients, and this correlation was stronger in patients whose tumors also had a mutation in the gene encoding p53. Thus, oncogenic Ras and TGF-beta signaling stimulate cancer progression through activation of the Delta Np63 transcriptional program.

Place, publisher, year, edition, pages
2016. Vol. 9, no 442, ra84
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-308949DOI: 10.1126/scisignal.aag3232ISI: 000387022100002PubMedID: 27555661OAI: oai:DiVA.org:uu-308949DiVA: diva2:1052838
Funder
Swedish Cancer Society, 100452Swedish Research Council, 2015-02757
Available from: 2016-12-07 Created: 2016-12-01 Last updated: 2016-12-07Bibliographically approved

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Vasilaki, EleftheriaSundqvist, AndersCedervall, JessicaOlsson, Anna-KarinMoustakas, AristidisHeldin, Carl-Henrik
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Ludwig Institute for Cancer ResearchScience for Life Laboratory, SciLifeLabDepartment of Medical Biochemistry and Microbiology
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