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FRMD6 has tumor suppressor functions in prostate cancer.
Haldrup, Jakob; Strand, Siri H; Cieza-Borrella, Clara; Jakobsson, Magnus E; Riedel, Maria; Norgaard, Maibritt; Hedensted, Stine; Dagnaes-Hansen, Frederik; Ulhoi, Benedicte Parm; Eeles, Rosalind; Borre, Michael; Olsen, Jesper V; Thomsen, Martin; Kote-Jarai, Zsofia; Sorensen, Karina D.
Afiliación
  • Haldrup J; Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
  • Strand SH; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
  • Cieza-Borrella C; Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
  • Jakobsson ME; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
  • Riedel M; Oncogenetics, Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
  • Norgaard M; Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark.
  • Hedensted S; Department of Immunotechnology, Lund University, Medicon Village, 22100, Lund, Sweden.
  • Dagnaes-Hansen F; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
  • Ulhoi BP; Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
  • Eeles R; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
  • Borre M; Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark.
  • Olsen JV; Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
  • Thomsen M; Department of Biomedicine, Aarhus University, Aarhus, Denmark.
  • Kote-Jarai Z; Institute of Pathology, Aarhus University Hospital, Aarhus, Denmark.
  • Sorensen KD; Oncogenetics, Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
Oncogene ; 40(4): 763-776, 2021 01.
Article en En | MEDLINE | ID: mdl-33249427
ABSTRACT
Available tools for prostate cancer (PC) prognosis are suboptimal but may be improved by better knowledge about genes driving tumor aggressiveness. Here, we identified FRMD6 (FERM domain-containing protein 6) as an aberrantly hypermethylated and significantly downregulated gene in PC. Low FRMD6 expression was associated with postoperative biochemical recurrence in two large PC patient cohorts. In overexpression and CRISPR/Cas9 knockout experiments in PC cell lines, FRMD6 inhibited viability, proliferation, cell cycle progression, colony formation, 3D spheroid growth, and tumor xenograft growth in mice. Transcriptomic, proteomic, and phospho-proteomic profiling revealed enrichment of Hippo/YAP and c-MYC signaling upon FRMD6 knockout. Connectivity Map analysis and drug repurposing experiments identified pyroxamide as a new potential therapy for FRMD6 deficient PC cells. Finally, we established orthotropic Frmd6 and Pten, or Pten only (control) knockout in the ROSA26 mouse prostate. After 12 weeks, Frmd6/Pten double knockouts presented high-grade prostatic intraepithelial neoplasia (HG-PIN) and hyperproliferation, while Pten single-knockouts developed only regular PIN lesions and displayed lower proliferation. In conclusion, FRMD6 was identified as a novel tumor suppressor gene and prognostic biomarker candidate in PC.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Próstata / Proteínas del Citoesqueleto / Proteínas Supresoras de Tumor / Péptidos y Proteínas de Señalización Intracelular / Proteínas de la Membrana Tipo de estudio: Prognostic_studies Límite: Aged / Animals / Humans / Male / Middle aged Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2021 Tipo del documento: Article País de afiliación: Dinamarca

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias de la Próstata / Proteínas del Citoesqueleto / Proteínas Supresoras de Tumor / Péptidos y Proteínas de Señalización Intracelular / Proteínas de la Membrana Tipo de estudio: Prognostic_studies Límite: Aged / Animals / Humans / Male / Middle aged Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2021 Tipo del documento: Article País de afiliación: Dinamarca
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