The collagen prolyl hydroxylases are bifunctional growth regulators in melanoma

Aithne Atkinson, Alexander Renziehausen, Hexiao Wang, Cristiana Lo Nigro, Laura Lattanzio, Marco Merlano, Bhavya Rao, Lynda Weir, Alan Evans, Rubeta Matin, Catherine Harwood, Peter Szlosarek, J Geoffrey Pickering, Colin Fleming, Van Ren Sim, Su Li, James T. Vasta, Ronald T. Raines, Mathieu Boniol, Alastair ThompsonCharlotte Proby, Tim Crook, Nelofer Syed

Research output: Contribution to journalArticle

6 Citations (Scopus)
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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.
Original languageEnglish
JournalJournal of Investigative Dermatology
Early online date16 Nov 2018
DOIs
Publication statusE-pub ahead of print - 16 Nov 2018

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Prolyl Hydroxylases
Melanoma
Collagen
Growth
Tumors
Hydroxylation
Methylation
Mixed Function Oxygenases
Processing
Neoplasms
Pharmacology

Keywords

  • Melanoma
  • Prolyl hydroxylases
  • methylation
  • epigenetics
  • biomarker

Cite this

Atkinson, A., Renziehausen, A., Wang, H., Nigro, C. L., Lattanzio, L., Merlano, M., ... Syed, N. (2018). The collagen prolyl hydroxylases are bifunctional growth regulators in melanoma. Journal of Investigative Dermatology. https://doi.org/10.1016/j.jid.2018.10.038
Atkinson, Aithne ; Renziehausen, Alexander ; Wang, Hexiao ; Nigro, Cristiana Lo ; Lattanzio, Laura ; Merlano, Marco ; Rao, Bhavya ; Weir, Lynda ; Evans, Alan ; Matin, Rubeta ; Harwood, Catherine ; Szlosarek, Peter ; Pickering, J Geoffrey ; Fleming, Colin ; Sim, Van Ren ; Li, Su ; Vasta, James T. ; Raines, Ronald T. ; Boniol, Mathieu ; Thompson, Alastair ; Proby, Charlotte ; Crook, Tim ; Syed, Nelofer. / The collagen prolyl hydroxylases are bifunctional growth regulators in melanoma. In: Journal of Investigative Dermatology. 2018.
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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.",
keywords = "Melanoma, Prolyl hydroxylases, methylation, epigenetics, biomarker",
author = "Aithne Atkinson and Alexander Renziehausen and Hexiao Wang and Nigro, {Cristiana Lo} and Laura Lattanzio and Marco Merlano and Bhavya Rao and Lynda Weir and Alan Evans and Rubeta Matin and Catherine Harwood and Peter Szlosarek and Pickering, {J Geoffrey} and Colin Fleming and Sim, {Van Ren} and Su Li and Vasta, {James T.} and Raines, {Ronald T.} and Mathieu Boniol and Alastair Thompson and Charlotte Proby and Tim Crook and Nelofer Syed",
note = "The study was supported by Melanoma Focus, The Leng Charitable Foundation, The Medical Research Council, The Tayside Tissue Bank and Barts and the London Charity. Work in RTR’s lab is supported by Grant R01 AR044276 (NIH). TC is Scottish Senior Clinical Fellow in Medical Oncology. Work in TC’s lab is supported by the Chief Scientist’s Office of Scotland, The Anonymous Trust, Tenovus Scotland and The Translational Medicine Research Fund of Dundee Cancer Centre. Work in NS’s lab is supported by The Brain Tumour Research Charity (BTRC). CP and LW are supported by Cancer Research UK. JGP holds the Heart and Stroke Foundation of Ontario / Barnett-Ivey Chair. AA is supported by the Sharon Dunster Fund.",
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Atkinson, A, Renziehausen, A, Wang, H, Nigro, CL, 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 2018, 'The collagen prolyl hydroxylases are bifunctional growth regulators in melanoma', Journal of Investigative Dermatology. https://doi.org/10.1016/j.jid.2018.10.038

The collagen prolyl hydroxylases are bifunctional growth regulators in melanoma. / Atkinson, Aithne; Renziehausen, Alexander; Wang, Hexiao; Nigro, Cristiana Lo; Lattanzio, Laura; Merlano, Marco; Rao, Bhavya; Weir, Lynda; Evans, Alan; Matin, Rubeta; Harwood, Catherine; Szlosarek, Peter; Pickering, J Geoffrey; Fleming, Colin; Sim, Van Ren; Li, Su; Vasta, James T.; Raines, Ronald T.; Boniol, Mathieu; Thompson, Alastair; Proby, Charlotte; Crook, Tim; Syed, Nelofer.

In: Journal of Investigative Dermatology, 16.11.2018.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The collagen prolyl hydroxylases are bifunctional growth regulators in melanoma

AU - Atkinson, Aithne

AU - Renziehausen, Alexander

AU - Wang, Hexiao

AU - Nigro, Cristiana Lo

AU - Lattanzio, Laura

AU - Merlano, Marco

AU - Rao, Bhavya

AU - Weir, Lynda

AU - Evans, Alan

AU - Matin, Rubeta

AU - Harwood, Catherine

AU - Szlosarek, Peter

AU - Pickering, J Geoffrey

AU - Fleming, Colin

AU - Sim, Van Ren

AU - Li, Su

AU - Vasta, James T.

AU - Raines, Ronald T.

AU - Boniol, Mathieu

AU - Thompson, Alastair

AU - Proby, Charlotte

AU - Crook, Tim

AU - Syed, Nelofer

N1 - The study was supported by Melanoma Focus, The Leng Charitable Foundation, The Medical Research Council, The Tayside Tissue Bank and Barts and the London Charity. Work in RTR’s lab is supported by Grant R01 AR044276 (NIH). TC is Scottish Senior Clinical Fellow in Medical Oncology. Work in TC’s lab is supported by the Chief Scientist’s Office of Scotland, The Anonymous Trust, Tenovus Scotland and The Translational Medicine Research Fund of Dundee Cancer Centre. Work in NS’s lab is supported by The Brain Tumour Research Charity (BTRC). CP and LW are supported by Cancer Research UK. JGP holds the Heart and Stroke Foundation of Ontario / Barnett-Ivey Chair. AA is supported by the Sharon Dunster Fund.

PY - 2018/11/16

Y1 - 2018/11/16

N2 - 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.

AB - 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.

KW - Melanoma

KW - Prolyl hydroxylases

KW - methylation

KW - epigenetics

KW - biomarker

U2 - 10.1016/j.jid.2018.10.038

DO - 10.1016/j.jid.2018.10.038

M3 - Article

C2 - 30452903

JO - Journal of Investigative Dermatology

JF - Journal of Investigative Dermatology

SN - 0022-202X

ER -