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

Research output: Contribution to journalArticle

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

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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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.

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