FRMD6 Has Tumor Suppressor Functions in Prostate Cancer

Overview

Journal Oncogene

Specialties Molecular Biology
Oncology

Date 2020 Nov 29

PMID 33249427

Citations 15

Authors

Jakob Haldrup

Siri H Strand

Clara Cieza-Borrella

Magnus E Jakobsson

Maria Riedel

Maibritt Norgaard

Stine Hedensted

Frederik Dagnaes-Hansen

Benedicte Parm Ulhoi

Rosalind Eeles

Michael Borre

Jesper V Olsen

Martin Thomsen

Zsofia Kote-Jarai

Karina D Sorensen

Affiliations

Soon will be listed here.

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.

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