FRMD6 has tumor suppressor functions in prostate cancer
- 28 November 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Oncogene
- Vol. 40 (4), 763-776
- https://doi.org/10.1038/s41388-020-01548-w
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.Funding Information
- Kræftens Bekæmpelse
- Novo Nordisk Fonden (NNF16OC0023048, NNF16OC0022946, NNF14CC0001)
- Det Frie Forskningsråd
- Aarhus Universitet
- The Harboe Foundation
- Richard and Debbi Burston, Nick Phillips and Bradshaw Foundation
- Lundbeckfonden (R231-2016-2682)
- National Institute of Health Research, The Biomedical Research Centre at the Institute of Cancer Research and Royal Marsden NHS Foundation Trust
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