NR2F1 controls tumour cell dormancy via SOX9- and RARβ-driven quiescence programmes

Maria Soledad Sosa, Falguni Parikh, Alexandre Gaspar Maia, Yeriel Estrada, Almudena Bosch, Paloma Bragado, Esther Ekpin, Ajish George, Yang Zheng, Hung-Ming Lam, Colm Morrissey, Chi-Yeh Chung, Eduardo F. Farias, Emily Bernstein and Julio A. Aguirre-Ghiso ()
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Maria Soledad Sosa: Mount Sinai School of Medicine
Falguni Parikh: Mount Sinai School of Medicine
Alexandre Gaspar Maia: Mount Sinai School of Medicine
Yeriel Estrada: Mount Sinai School of Medicine
Almudena Bosch: Mount Sinai School of Medicine
Paloma Bragado: Mount Sinai School of Medicine
Esther Ekpin: Mount Sinai School of Medicine
Ajish George: Mount Sinai School of Medicine
Yang Zheng: Mount Sinai School of Medicine
Hung-Ming Lam: University of Washington
Colm Morrissey: University of Washington
Chi-Yeh Chung: Mount Sinai School of Medicine
Eduardo F. Farias: Mount Sinai School of Medicine
Emily Bernstein: Mount Sinai School of Medicine
Julio A. Aguirre-Ghiso: Mount Sinai School of Medicine

Nature Communications, 2015, vol. 6, issue 1, 1-14

Abstract: Abstract Metastases can originate from disseminated tumour cells (DTCs), which may be dormant for years before reactivation. Here we find that the orphan nuclear receptor NR2F1 is epigenetically upregulated in experimental head and neck squamous cell carcinoma (HNSCC) dormancy models and in DTCs from prostate cancer patients carrying dormant disease for 7–18 years. NR2F1-dependent dormancy is recapitulated by a co-treatment with the DNA-demethylating agent 5-Aza-C and retinoic acid across various cancer types. NR2F1-induced quiescence is dependent on SOX9, RARβ and CDK inhibitors. Intriguingly, NR2F1 induces global chromatin repression and the pluripotency gene NANOG, which contributes to dormancy of DTCs in the bone marrow. When NR2F1 is blocked in vivo, growth arrest or survival of dormant DTCs is interrupted in different organs. We conclude that NR2F1 is a critical node in dormancy induction and maintenance by integrating epigenetic programmes of quiescence and survival in DTCs.

Date: 2015
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DOI: 10.1038/ncomms7170

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