Oncometabolite induced primary cilia loss in pheochromocytoma

O'Toole, Samuel M., Watson, David S., Novoselova, Tatiana ORCID: https://orcid.org/0000-0002-2394-4667, Romano, Lisa E. L., King, Peter J., Bradshaw, Teisha Y., Thompson, Claire L., Knight, Martin M., Sharp, Tyson V., Barnes, Michael R., Srirangalingam, Umasuthan, Drake, William M. and Chapple, J. Paul (2019) Oncometabolite induced primary cilia loss in pheochromocytoma. Endocrine-Related Cancer, 26 (1) . pp. 165-180. ISSN 1351-0088 [Article] (doi:10.1530/ERC-18-0134)

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Abstract

Primary cilia are sensory organelles involved in regulation of cellular signaling. Cilia loss is frequently observed in tumors; yet, the responsible mechanisms and consequences for tumorigenesis remain unclear. We demonstrate that cilia structure and function is disrupted in human pheochromocytomas – endocrine tumors of the adrenal medulla. This is concomitant with transcriptional changes within cilia-mediated signaling pathways that are associated with tumorigenesis generally and pheochromocytomas specifically. Importantly, cilia loss was most dramatic in patients with germline mutations in the pseudohypoxia-linked genes SDHx and VHL. Using a pheochromocytoma cell line derived from rat, we show that hypoxia and oncometabolite-induced pseudohypoxia are key drivers of cilia loss and identify that this is dependent on activation of an Aurora-A/HDAC6 cilia resorption pathway. We also show cilia loss drives dramatic transcriptional changes associated with proliferation and tumorigenesis. Our data provide evidence for primary cilia dysfunction contributing to pathogenesis of pheochromocytoma by a hypoxic/pseudohypoxic mechanism and implicates oncometabolites as ciliary regulators. This is important as pheochromocytomas can cause mortality by mechanisms including catecholamine production and malignant transformation, while hypoxia is a general feature of solid tumors. Moreover, pseudohypoxia-induced cilia resorption can be pharmacologically inhibited, suggesting potential for therapeutic intervention.

Item Type: Article
Research Areas: A. > School of Science and Technology > Natural Sciences
Item ID: 28124
Notes on copyright: © 2018 The authors 2018.
Published by Bioscientifica Ltd.
This work is licensed under a Creative Commons Attribution 4.0 International License.
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Depositing User: Tatiana Novoselova
Date Deposited: 08 Nov 2019 12:55
Last Modified: 20 Aug 2020 22:22
URI: https://eprints.mdx.ac.uk/id/eprint/28124

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