Comisso E, Scarola M, Rosso M, Piazza S, Marzinotto S, Ciani Y, Orsaria M, Mariuzzi L, Schneider C, Schoeftner S, Benetti R
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.
Oncogene. 2017 Jul 27;36(30):4253-4266. doi: 10.1038/onc.2017.20. Epub 2017 Mar 20.
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.
八聚体结合转录因子4（OCT4）对胚胎干细胞的自我更新至关重要。在此我们表明，OCT4通过使视网膜母细胞瘤肿瘤抑制通路失活并增强癌细胞的有丝分裂稳定性，增加了高级别浆液性卵巢癌（HG-SOC）的侵袭性。OCT4驱动蛋白磷酸酶1核抑制剂（NIPP1）和细胞周期蛋白F（CCNF）的表达，它们共同抑制蛋白磷酸酶1（PP1）。这导致视网膜母细胞瘤蛋白（pRB）过度磷酸化、细胞增殖加速以及卵巢癌细胞体外致瘤性增加。同时，OCT4和NIPP1/CCNF驱动中心染色体乘客复合体（CPC）组分Borealin、生存素和有丝分裂激酶极光激酶B的表达，促进多余中心体的聚集以增加有丝分裂稳定性。OCT4或NIPP1/CCNF的缺失会导致严重的有丝分裂缺陷、多极纺锤体和多余中心体，最终导致细胞凋亡的诱导。这些表型在不同的癌症模型中得到重现，表明对人类癌症具有普遍相关性。重要的是，这些平行通路的激活导致HG-SOC患者的总生存率显著降低。总之，我们的数据突出了OCT4作为有丝分裂保真度和RB肿瘤抑制通路活性的核心调节因子的前所未有的作用。破坏这一通路代表了一种针对HG-SOC细胞侵袭性子群体的有前景的策略。
