OCT4 controls mitotic stability and inactivates the RB tumor suppressor pathway to enhance ovarian cancer aggressiveness.
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.
Cancer Epigenetic Group, Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie (LNCIB), Area Science Park, Trieste, Italy.|Department of Medical and Biological Sciences, University of Udine; Udine, Italy.
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Comisso
Cancer Epigenetic Group, Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie (LNCIB), Area Science Park, Trieste, Italy.
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Scarola
Cancer Epigenetic Group, Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie (LNCIB), Area Science Park, Trieste, Italy.|Department for Life Sciences, University of Trieste, Trieste, Italy.
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Rosso
Cancer Epigenetic Group, Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie (LNCIB), Area Science Park, Trieste, Italy.|Centre for Integrative Biology, University of Trento (CIBIO), Trento, Italy.
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Piazza
Department of Medical and Biological Science, Institute of Anatomic Pathology, University Hospital of Udine, Udine, Italy.
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Marzinotto
Cancer Epigenetic Group, Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie (LNCIB), Area Science Park, Trieste, Italy.
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Ciani
Department of Medical and Biological Science, Institute of Anatomic Pathology, University Hospital of Udine, Udine, Italy.
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Orsaria
Department of Medical and Biological Science, Institute of Anatomic Pathology, University Hospital of Udine, Udine, Italy.
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Mariuzzi
Cancer Epigenetic Group, Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie (LNCIB), Area Science Park, Trieste, Italy.|Department of Medical and Biological Sciences, University of Udine; Udine, Italy.
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Schneider
Cancer Epigenetic Group, Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie (LNCIB), Area Science Park, Trieste, Italy.|Department for Life Sciences, University of Trieste, Trieste, Italy.
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Schoeftner
Cancer Epigenetic Group, Laboratorio Nazionale Consorzio Interuniversitario Biotecnologie (LNCIB), Area Science Park, Trieste, Italy.|Department of Medical and Biological Sciences, University of Udine; Udine, Italy.
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Benetti
D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D018284:Cystadenocarcinoma, Serous / Q000473:pathology*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D018613:Microscopy, Confocal; D008938:Mitosis / Q000502:physiology*; D009361:Neoplasm Invasiveness / Q000473:pathology; D050814:Octamer Transcription Factor-3 / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D016160:Retinoblastoma Protein