FRMD6 has tumor suppressor functions in prostate cancer
| Autor: | Jakob Haldrup, Magnus E. Jakobsson, Benedicte Parm Ulhøi, Stine Hedensted, Martin K. Thomsen, Siri H. Strand, Zsofia Kote-Jarai, Maria Riedel, Clara Cieza-Borrella, Jesper V. Olsen, Karina Dalsgaard Sørensen, Rosalind A. Eeles, Michael Borre, Maibritt Nørgaard, Frederik Dagnæs-Hansen |
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| Rok vydání: | 2020 |
| Předmět: |
Male
0301 basic medicine Cancer Research TOPHAT Tumor suppressor gene Aminopyridines Down-Regulation Protein Serine-Threonine Kinases Biology Hydroxamic Acids Transcriptome Mice 03 medical and health sciences Prostate cancer 0302 clinical medicine Genetics medicine Animals Humans YAP/TAZ PTEN Hippo Signaling Pathway Promoter Regions Genetic Molecular Biology Gene knockout Aged Cell Proliferation Cell growth Tumor Suppressor Proteins Intracellular Signaling Peptides and Proteins PTEN Phosphohydrolase Membrane Proteins Prostatic Neoplasms DNA Methylation Middle Aged Prognosis medicine.disease GENE Cytoskeletal Proteins 030104 developmental biology WILLIN 030220 oncology & carcinogenesis DNA methylation Cancer research biology.protein Pyroxamide EXPRESSION ANALYSIS |
| Zdroj: | Haldrup, J, Strand, S H, Cieza-Borrella, C, Jakobsson, M E, Riedel, M, Norgaard, M, Hedensted, S, Dagnaes-Hansen, F, Ulhoi, B P, Eeles, R, Borre, M, Olsen, J V, Thomsen, M, Kote-Jarai, Z & Sorensen, K D 2021, ' FRMD6 has tumor suppressor functions in prostate cancer ', Oncogene, vol. 40, no. 4, pp. 763–776 . https://doi.org/10.1038/s41388-020-01548-w Haldrup, J, Strand, S H, Cieza-Borrella, C, Jakobsson, M E, Riedel, M, Norgaard, M, Hedensted, S, Dagnaes-Hansen, F, Ulhoi, B P, Eeles, R, Borre, M, Olsen, J, Thomsen, M, Kote-Jarai, Z & Sorensen, K D 2021, ' FRMD6 has tumor suppressor functions in prostate cancer ', Oncogene, vol. 40, pp. 763-776 . https://doi.org/10.1038/s41388-020-01548-w |
| ISSN: | 1476-5594 0950-9232 |
| DOI: | 10.1038/s41388-020-01548-w |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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