Collagen Prolyl Hydroxylases Are Bifunctional Growth Regulators in Melanoma
Appropriate post-translational processing of collagen requires prolyl hydroxylation, catalyzed by collagen prolyl 3-hydroxylase and collagen prolyl 4-hydroxylase, and is essential for normal cell function. Here we have investigated the expression, transcriptional regulation, and function of the coll...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier Science Ltd.
2020
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| Online Access: | https://hdl.handle.net/1721.1/123511 |
| _version_ | 1826209570274410496 |
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| author | Atkinson, Aithne Renziehausen, Alexander Wang, Hexiao Lo Nigro, Cristiana 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 |
| author2 | Massachusetts Institute of Technology. Department of Chemistry |
| author_facet | Massachusetts Institute of Technology. Department of Chemistry Atkinson, Aithne Renziehausen, Alexander Wang, Hexiao Lo Nigro, Cristiana 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 |
| author_sort | Atkinson, Aithne |
| collection | MIT |
| description | Appropriate post-translational processing of collagen requires prolyl hydroxylation, catalyzed by collagen prolyl 3-hydroxylase and collagen prolyl 4-hydroxylase, and is essential for normal cell function. Here we have investigated the expression, transcriptional regulation, and function of the collagen prolyl 3-hydroxylase and collagen prolyl 4-hydroxylase families in melanoma. We show that the collagen prolyl 3-hydroxylase family exemplified by Leprel1 and Leprel2 is subject to methylation-dependent transcriptional silencing in primary and metastatic melanoma consistent with a tumor suppressor function. In contrast, although there is transcriptional silencing of P4HA3 in a subset of melanomas, the collagen prolyl 4-hydroxylase family members P4HA1, P4HA2, and P4HA3 are often overexpressed in melanoma, expression being prognostic of worse clinical outcomes. Consistent with tumor 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 collagen prolyl 4-hydroxylase inhibitors reduces proliferation and inhibits invasiveness of melanoma cells. Together, our data identify the collagen prolyl 3-hydroxylase and collagen prolyl 4-hydroxylase families as potentially important regulators of melanoma growth and invasiveness and suggest that selective inhibition of collagen prolyl 4-hydroxylase is an attractive strategy to reduce the invasive properties of melanoma cells. |
| first_indexed | 2024-09-23T14:24:34Z |
| format | Article |
| id | mit-1721.1/123511 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T14:24:34Z |
| publishDate | 2020 |
| publisher | Elsevier Science Ltd. |
| record_format | dspace |
| spelling | mit-1721.1/1235112022-10-01T21:11:22Z Collagen Prolyl Hydroxylases Are Bifunctional Growth Regulators in Melanoma Atkinson, Aithne Renziehausen, Alexander Wang, Hexiao Lo Nigro, Cristiana 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 Massachusetts Institute of Technology. Department of Chemistry Cell Biology Biochemistry Molecular Biology Dermatology Appropriate post-translational processing of collagen requires prolyl hydroxylation, catalyzed by collagen prolyl 3-hydroxylase and collagen prolyl 4-hydroxylase, and is essential for normal cell function. Here we have investigated the expression, transcriptional regulation, and function of the collagen prolyl 3-hydroxylase and collagen prolyl 4-hydroxylase families in melanoma. We show that the collagen prolyl 3-hydroxylase family exemplified by Leprel1 and Leprel2 is subject to methylation-dependent transcriptional silencing in primary and metastatic melanoma consistent with a tumor suppressor function. In contrast, although there is transcriptional silencing of P4HA3 in a subset of melanomas, the collagen prolyl 4-hydroxylase family members P4HA1, P4HA2, and P4HA3 are often overexpressed in melanoma, expression being prognostic of worse clinical outcomes. Consistent with tumor 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 collagen prolyl 4-hydroxylase inhibitors reduces proliferation and inhibits invasiveness of melanoma cells. Together, our data identify the collagen prolyl 3-hydroxylase and collagen prolyl 4-hydroxylase families as potentially important regulators of melanoma growth and invasiveness and suggest that selective inhibition of collagen prolyl 4-hydroxylase is an attractive strategy to reduce the invasive properties of melanoma cells. National Institute of Health (U.S.) (Grant R01 AR044276) 2020-01-21T21:14:13Z 2020-01-21T21:14:13Z 2018-11-16 2017-09-16 2020-01-07T17:57:35Z Article http://purl.org/eprint/type/JournalArticle 0022-202X 1523-1747 https://hdl.handle.net/1721.1/123511 Atkinson, Aithne et al. "Collagen Prolyl Hydroxylases Are Bifunctional Growth Regulators in Melanoma." Journal of Investigative Dermatology, 139, 5, (May 2019): 1118-1126 © 2018 The Authors en https://doi.org/10.1016/j.jid.2018.10.038 Journal of Investigative Dermatology Creative Commons Attribution-NonCommercial-NoDerivs License http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier Science Ltd. Other repository |
| spellingShingle | Cell Biology Biochemistry Molecular Biology Dermatology Atkinson, Aithne Renziehausen, Alexander Wang, Hexiao Lo Nigro, Cristiana 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 Collagen Prolyl Hydroxylases Are Bifunctional Growth Regulators in Melanoma |
| title | Collagen Prolyl Hydroxylases Are Bifunctional Growth Regulators in Melanoma |
| title_full | Collagen Prolyl Hydroxylases Are Bifunctional Growth Regulators in Melanoma |
| title_fullStr | Collagen Prolyl Hydroxylases Are Bifunctional Growth Regulators in Melanoma |
| title_full_unstemmed | Collagen Prolyl Hydroxylases Are Bifunctional Growth Regulators in Melanoma |
| title_short | Collagen Prolyl Hydroxylases Are Bifunctional Growth Regulators in Melanoma |
| title_sort | collagen prolyl hydroxylases are bifunctional growth regulators in melanoma |
| topic | Cell Biology Biochemistry Molecular Biology Dermatology |
| url | https://hdl.handle.net/1721.1/123511 |
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