FRMD6 has tumor suppressor functions in prostate cancer

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Jakob Haldrup
  • Siri H Strand
  • Clara Cieza-Borrella, Institute of Cancer Research, London
  • ,
  • Magnus E Jakobsson, University of Copenhagen, Lund University
  • ,
  • Maria Riedel
  • ,
  • Maibritt Norgaard
  • Stine Hedensted
  • ,
  • Frederik Dagnaes-Hansen
  • ,
  • Benedicte Parm Ulhoi
  • ,
  • Rosalind Eeles, Institute of Cancer Research, London
  • ,
  • Michael Borre
  • Jesper V Olsen, University of Copenhagen
  • ,
  • Martin Thomsen
  • Zsofia Kote-Jarai, Institute of Cancer Research, London
  • ,
  • Karina D Sorensen

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.

Original languageEnglish
JournalOncogene
Volume40
Issue4
Pages (from-to)763–776
ISSN0950-9232
DOIs
Publication statusPublished - Jan 2021

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