Cytoplasmic PML promotes TGF-β-associated epithelial–mesenchymal transition and invasion in prostate cancer

Buczek, ME, Miles, AK ORCID: https://orcid.org/0000-0002-5388-938X, Green, W, Johnson, C, Boocock, DJ ORCID: https://orcid.org/0000-0002-7333-3549, Pockley, AG ORCID: https://orcid.org/0000-0001-9593-6431, Rees, RC ORCID: https://orcid.org/0000-0002-4574-4746, Hulman, G, Van Schalkwyk, G, Parkinson, R, Hulman, J, Powe, DG and Regad, T ORCID: https://orcid.org/0000-0003-4028-6368, 2016. Cytoplasmic PML promotes TGF-β-associated epithelial–mesenchymal transition and invasion in prostate cancer. Oncogene, 35, pp. 3465-3475. ISSN 0950-9232

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Abstract

Epithelial–mesenchymal transition (EMT) is a key event that is involved in the invasion and dissemination of cancer cells. Although typically considered as having tumour-suppressive properties, transforming growth factor (TGF)-β signalling is altered during cancer and has been associated with the invasion of cancer cells and metastasis. In this study, we report a previously unknown role for the cytoplasmic promyelocytic leukaemia (cPML) tumour suppressor in TGF-β signalling-induced regulation of prostate cancer-associated EMT and invasion. We demonstrate that cPML promotes a mesenchymal phenotype and increases the invasiveness of prostate cancer cells. This event is associated with activation of TGF-β canonical signalling pathway through the induction of Sma and Mad related family 2 and 3 (SMAD2 and SMAD3) phosphorylation. Furthermore, the cytoplasmic localization of promyelocytic leukaemia (PML) is mediated by its nuclear export in a chromosomal maintenance 1 (CRM1)-dependent manner. This was clinically tested in prostate cancer tissue and shown that cytoplasmic PML and CRM1 co-expression correlates with reduced disease-specific survival. In summary, we provide evidence of dysfunctional TGF-β signalling occurring at an early stage in prostate cancer. We show that this disease pathway is mediated by cPML and CRM1 and results in a more aggressive cancer cell phenotype. We propose that the targeting of this pathway could be therapeutically exploited for clinical benefit.

Item Type:	Journal article
Publication Title:	Oncogene
Creators:	Buczek, M.E., Miles, A.K., Green, W., Johnson, C., Boocock, D.J., Pockley, A.G., Rees, R.C., Hulman, G., Van Schalkwyk, G., Parkinson, R., Hulman, J., Powe, D.G. and Regad, T.
Publisher:	Nature Publishing Group
Date:	2016
Volume:	35
ISSN:	0950-9232
Identifiers:	Number Type 10.1038/onc.2015.409 DOI onc2015409 Publisher Item Identifier
Rights:	© 2015 Macmillan Publishers Limited. All rights reserved. OPEN.
Divisions:	Schools > School of Science and Technology
Record created by:	Jill Tomkinson
Date Added:	24 Nov 2015 14:35
Last Modified:	11 Oct 2021 13:25
URI:	https://irep.ntu.ac.uk/id/eprint/26466

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