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OCT4 controls mitotic stability and inactivates the RB tumor suppressor pathway to enhance ovarian cancer aggressiveness

Oncogene volume 36, pages 4253–4266 (2017)Cite this article

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Abstract

OCT4 (Octamer-binding transcription factor 4) is essential for embryonic stem cell self-renewal. Here we show that OCT4 increases the aggressiveness of high-grade serous ovarian cancer (HG-SOC) by inactivating the Retinoblastoma tumor suppressor pathway and enhancing mitotic stability in cancer cells. OCT4 drives the expression of Nuclear Inhibitor of Protein Phosphatase type 1 (NIPP1) and Cyclin F (CCNF) that together inhibit Protein Phosphatase 1 (PP1). This results in pRB hyper-phosphorylation, accelerated cell proliferation and increased in vitro tumorigenicity of ovarian cancer cells. In parallel, OCT4 and NIPP1/CCNF drive the expression of the central Chromosomal Passenger Complex (CPC) components, Borealin, Survivin and the mitotic kinase Aurora B, promoting the clustering of supernumerary centrosomes to increase mitotic stability. Loss of OCT4 or NIPP1/CCNF results in severe mitotic defects, multipolar spindles and supernumerary centrosomes, finally leading to the induction of apoptosis. These phenotypes were recapitulated in different cancer models indicating general relevance for human cancer. Importantly, activation of these parallel pathways leads to dramatically reduced overall survival of HG-SOC patients. Altogether, our data highlights an unprecedented role for OCT4 as central regulator of mitotic fidelity and RB tumor suppressor pathway activity. Disrupting this pathway represents a promising strategy to target an aggressive subpopulation of HG-SOC cells.

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Acknowledgements

We thank Angelica Feresin and Simone Pisano (University of Udine, Italy) for helping with processing of patient samples and with spindle defects experiments. EC and MS are AIRC post-doctoral fellows. MR is enrolled in the PhD program for Molecular Medicine at the University of Trieste. This work was supported by an AIRC grant (Rif 17756 to RB and Rif 10299 to SS), a financial support by the Rotary Club Bari Sud to RB and a grant from the Italian Ministry of Education, Universities and Research (MIUR) CTN01_00177_817708 to CS.

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Author notes

  1. M Scarola and M Rosso: These authors contributed equally to this work.

Authors and Affiliations

  1. Cancer Epigenetic Group, Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie (LNCIB), Area Science Park, Trieste, Italy

    E Comisso, M Scarola, M Rosso, S Piazza, Y Ciani, C Schneider, S Schoeftner & R Benetti

  2. Department of Medical and Biological Sciences, University of Udine,

    E Comisso, C Schneider & R Benetti

  3. Udine, Italy

    E Comisso, C Schneider & R Benetti

  4. Department for Life Sciences, University of Trieste, Trieste, Italy

    M Rosso & S Schoeftner

  5. Centre for Integrative Biology, University of Trento (CIBIO), Trento, Italy,

    S Piazza

  6. Department of Medical and Biological Science, Institute of Anatomic Pathology, University Hospital of Udine, Udine, Italy

    S Marzinotto, M Orsaria & L Mariuzzi

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  1. E Comisso
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Correspondence to S Schoeftner or R Benetti.

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Comisso, E., Scarola, M., Rosso, M. et al. OCT4 controls mitotic stability and inactivates the RB tumor suppressor pathway to enhance ovarian cancer aggressiveness. Oncogene 36, 4253–4266 (2017). https://doi.org/10.1038/onc.2017.20

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