The collagen prolyl hydroxylases are bifunctional growth regulators in melanoma

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Title: The collagen prolyl hydroxylases are bifunctional growth regulators in melanoma
Author(s): Atkinson, A
Renziehausen, A
Wang, H
Lo Nigro, C
Lattanzio, L
Merlano, M
Rao, B
Weir, L
Evans, A
Matin, R
Harwood, C
Szlosarek, P
Pickering, JG
Fleming, C
Sim, VR
Li, S
Vasta, JT
Raines, RT
Boniol, M
Thompson, A
Proby, C
Crook, T
Syed, N
Item Type: Journal Article
Abstract: Appropriate post-translational processing of collagen requires prolyl hydroxylation, catalyzed by the prolyl 3- (C-P3H) and prolyl 4- (C-P4H) hydroxylases is essential for normal cell function. Here we have investigated the expression, transcriptional regulation and function of the C-P3H and C-P4H families in melanoma. We show that the CP3H family exemplified by Leprel1 and Leprel2 are subject to methylation-dependent transcriptional silencing in primary and metastatic melanoma consistent with a tumour suppressor function. In contrast, although there is transcriptional silencing of P4HA3 in a sub-set of melanomas, the CP4H family members P4HA1, P4HA2 and P4HA3 are often over-expressed in melanoma, expression being prognostic of worse clinical outcomes. Consistent with tumour suppressor function, ectopic expression of Leprel1 and Leprel2 inhibits melanoma proliferation, whereas P4HA2 and P4HA3 increase proliferation and particularly invasiveness of melanoma cells. Pharmacological inhibition with multiple selective C-P4H inhibitors reduces proliferation and inhibits invasiveness of melanoma cells. Together, our data identify the C-P3H and C-P4H families as potentially important regulators of melanoma growth and invasiveness and suggest that selective inhibition of C-P4H is an attractive strategy to reduce the invasive properties of melanoma cells.
Publication Date: 16-Nov-2018
Date of Acceptance: 1-Oct-2018
URI: http://hdl.handle.net/10044/1/65729
DOI: https://dx.doi.org/10.1016/j.jid.2018.10.038
ISSN: 0022-202X
Publisher: Elsevier
Journal / Book Title: Journal of Investigative Dermatology
Sponsor/Funder: Brain Tumour Research Campaign
Funder's Grant Number: N/A
Copyright Statement: © 2018 The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology.
Keywords: Melanoma
Prolyl hydroxylases
biomarker
epigenetics
methylation
Melanoma
Prolyl hydroxylases
biomarker
epigenetics
methylation
1103 Clinical Sciences
1112 Oncology And Carcinogenesis
Dermatology & Venereal Diseases
Publication Status: Published online
Conference Place: United States
Embargo Date: 2019-11-16
Online Publication Date: 2018-11-16
Appears in Collections:Department of Medicine
Faculty of Medicine



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