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

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 promo...

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Autores principales: De Piano, Mario, Manuelli, Valeria, Zadra, Giorgia, Otte, Jonathan, Edqvist, Per-Henrik D., Pontén, Fredrik, Nowinski, Salpie, Niaouris, Athanasios, Grigoriadis, Anita, Loda, Massimo, Van Hemelrijck, Mieke, Wells, Claire M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190568/
https://www.ncbi.nlm.nih.gov/pubmed/32139877
http://dx.doi.org/10.1038/s41388-020-1243-2
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author De Piano, Mario
Manuelli, Valeria
Zadra, Giorgia
Otte, Jonathan
Edqvist, Per-Henrik D.
Pontén, Fredrik
Nowinski, Salpie
Niaouris, Athanasios
Grigoriadis, Anita
Loda, Massimo
Van Hemelrijck, Mieke
Wells, Claire M.
author_facet De Piano, Mario
Manuelli, Valeria
Zadra, Giorgia
Otte, Jonathan
Edqvist, Per-Henrik D.
Pontén, Fredrik
Nowinski, Salpie
Niaouris, Athanasios
Grigoriadis, Anita
Loda, Massimo
Van Hemelrijck, Mieke
Wells, Claire M.
author_sort De Piano, Mario
collection PubMed
description 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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spelling pubmed-71905682020-05-04 Lipogenic signalling modulates prostate cancer cell adhesion and migration via modification of Rho GTPases De Piano, Mario Manuelli, Valeria Zadra, Giorgia Otte, Jonathan Edqvist, Per-Henrik D. Pontén, Fredrik Nowinski, Salpie Niaouris, Athanasios Grigoriadis, Anita Loda, Massimo Van Hemelrijck, Mieke Wells, Claire M. Oncogene Article 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. Nature Publishing Group UK 2020-03-05 2020 /pmc/articles/PMC7190568/ /pubmed/32139877 http://dx.doi.org/10.1038/s41388-020-1243-2 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
De Piano, Mario
Manuelli, Valeria
Zadra, Giorgia
Otte, Jonathan
Edqvist, Per-Henrik D.
Pontén, Fredrik
Nowinski, Salpie
Niaouris, Athanasios
Grigoriadis, Anita
Loda, Massimo
Van Hemelrijck, Mieke
Wells, Claire M.
Lipogenic signalling modulates prostate cancer cell adhesion and migration via modification of Rho GTPases
title Lipogenic signalling modulates prostate cancer cell adhesion and migration via modification of Rho GTPases
title_full Lipogenic signalling modulates prostate cancer cell adhesion and migration via modification of Rho GTPases
title_fullStr Lipogenic signalling modulates prostate cancer cell adhesion and migration via modification of Rho GTPases
title_full_unstemmed Lipogenic signalling modulates prostate cancer cell adhesion and migration via modification of Rho GTPases
title_short Lipogenic signalling modulates prostate cancer cell adhesion and migration via modification of Rho GTPases
title_sort lipogenic signalling modulates prostate cancer cell adhesion and migration via modification of rho gtpases
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190568/
https://www.ncbi.nlm.nih.gov/pubmed/32139877
http://dx.doi.org/10.1038/s41388-020-1243-2
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