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RASSF1A disrupts the NOTCH signaling axis via SNURF/RNF4-mediated ubiquitination of HES1.
Papaspyropoulos, Angelos; Angelopoulou, Andriani; Mourkioti, Ioanna; Polyzou, Aikaterini; Pankova, Daniela; Toskas, Konstantinos; Lanfredini, Simone; Pantazaki, Anastasia A; Lagopati, Nefeli; Kotsinas, Athanassios; Evangelou, Konstantinos; Chronopoulos, Efstathios; O'Neill, Eric; Gorgoulis, Vassilis.
Afiliación
  • Papaspyropoulos A; Department of Oncology, University of Oxford, Oxford, UK.
  • Angelopoulou A; Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National Kapodistrian University of Athens (NKUA), Athens, Greece.
  • Mourkioti I; Biomedical Research Foundation, Academy of Athens, Athens, Greece.
  • Polyzou A; Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National Kapodistrian University of Athens (NKUA), Athens, Greece.
  • Pankova D; Biomedical Research Foundation, Academy of Athens, Athens, Greece.
  • Toskas K; Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National Kapodistrian University of Athens (NKUA), Athens, Greece.
  • Lanfredini S; Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National Kapodistrian University of Athens (NKUA), Athens, Greece.
  • Pantazaki AA; Department of Oncology, University of Oxford, Oxford, UK.
  • Lagopati N; Department of Oncology, University of Oxford, Oxford, UK.
  • Kotsinas A; Department of Oncology, University of Oxford, Oxford, UK.
  • Evangelou K; Laboratory of Biochemistry, Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki, Greece.
  • Chronopoulos E; Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National Kapodistrian University of Athens (NKUA), Athens, Greece.
  • O'Neill E; Biomedical Research Foundation, Academy of Athens, Athens, Greece.
  • Gorgoulis V; Molecular Carcinogenesis Group, Department of Histology and Embryology, School of Medicine, National Kapodistrian University of Athens (NKUA), Athens, Greece.
EMBO Rep ; 23(2): e51287, 2022 02 03.
Article en En | MEDLINE | ID: mdl-34897944
RASSF1A promoter methylation has been correlated with tumor dedifferentiation and aggressive oncogenic behavior. Nevertheless, the underlying mechanism of RASSF1A-dependent tumor dedifferentiation remains elusive. Here, we show that RASSF1A directly uncouples the NOTCH-HES1 axis, a key suppressor of differentiation. Interestingly, the crosstalk of RASSF1A with HES1 occurs independently from the signaling route connecting RASSF1A with the Hippo pathway. At the molecular level, we demonstrate that RASSF1A acts as a scaffold essential for the SUMO-targeted E3 ligase SNURF/RNF4 to target HES1 for degradation. The reciprocal relationship between RASSF1A and HES1 is evident across a wide range of human tumors, highlighting the clinical significance of the identified pathway. We show that HES1 upregulation in a RASSF1A-depleted environment renders cells non-responsive to the downstream effects of γ-secretase inhibitors (GSIs) which restrict signaling at the level of the NOTCH receptor. Taken together, we report a mechanism through which RASSF1A exerts autonomous regulation of the critical Notch effector HES1, thus classifying RASSF1A expression as an integral determinant of the clinical effectiveness of Notch inhibitors.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Proteínas Supresoras de Tumor / Receptores Notch / Factor de Transcripción HES-1 Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: EMBO Rep Asunto de la revista: BIOLOGIA MOLECULAR Año: 2022 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Transducción de Señal / Proteínas Supresoras de Tumor / Receptores Notch / Factor de Transcripción HES-1 Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: EMBO Rep Asunto de la revista: BIOLOGIA MOLECULAR Año: 2022 Tipo del documento: Article Pais de publicación: Reino Unido