Lipogenic signalling modulates prostate cancer cell adhesion and migration via modification of Rho GTPases

Mario De Piano, Valeria Manuelli, Giorgia Zadra, Jonathan Otte, Per-Henrik Edqvist, Fredrik Ponten, Salpi Nowinski, Athanasios Niaouris, Anita Grigoriadis, Massimo Loda, Mieke Van Hemelrijck, Claire M Wells

Research output: Contribution to journalArticlepeer-review

36 Citations (Scopus)
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Abstract

Fatty acid synthase (FASN) is commonly overexpressed in prostate cancer and associated with tumour progression. FASN is responsible for de novo synthesis of the fatty acid palmitate; the building block for protein palmitoylation. Recent work has suggested that alongside its established role in promoting cell proliferation FASN may also promote invasion. We now find depletion of FASN expression increases prostate cancer cell adhesiveness, impairs HGF-mediated cell migration and reduces 3D invasion. These changes in motility suggest that FASN can mediate actin cytoskeletal remodelling; a process known to be downstream of Rho family GTPases. Here, we demonstrate that modulation of FASN expression specifically impacts on the palmitoylation of the atypical GTPase RhoU. Impaired RhoU activity in FASN depleted cells leads to reduced adhesion turnover downstream of paxillin serine phosphorylation, which is rescued by addition of exogenous palmitate. Moreover, canonical Cdc42 expression is dependent on the palmitoylation status of RhoU. Thus we uncover a novel relationship between FASN, RhoU and Cdc42 that directly influences cell migration potential. These results provide compelling evidence that FASN activity directly promotes cell migration and supports FASN as a potential therapeutic target in metastatic prostate cancer.
Original languageEnglish
Pages (from-to)3666–3679
Number of pages14
JournalOncogene
Volume39
Issue number18
Early online date5 Mar 2020
DOIs
Publication statusPublished - 30 Apr 2020

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