期刊
ONCOGENE
卷 40, 期 4, 页码 763-776出版社
SPRINGERNATURE
DOI: 10.1038/s41388-020-01548-w
关键词
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资金
- Royal Marsden NHS Foundation Trust
- de Laszlo Foundation
- Danish Cancer Society
- Velux Foundation (KDS)
- Novo Nordisk Foundation [NNF16OC0023048, NNF16OC0022946, NNF14CC0001]
- Independent Research Fund Denmark, The Harboe Foundation
- Lundbeck Foundation [R231-2016-2682]
- National Institute of Health Research
- Aarhus University
- NIHR
FRMD6 has been identified as a novel tumor suppressor gene and prognostic biomarker candidate in prostate cancer, with its low expression associated with postoperative biochemical recurrence. It inhibits functions and growth of PC cells, leading to enrichment of Hippo/YAP and c-MYC signaling pathways upon knockout, ultimately causing prostatic intraepithelial neoplasia and hyperproliferation.
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.
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