O'Toole, SM;
Watson, DS;
Novoselova, TV;
Romano, LEL;
King, PJ;
Bradshaw, TY;
Thompson, CL;
... Chapple, JP; + view all
(2019)
Oncometabolite induced primary cilia loss in pheochromocytoma.
Endocrine-Related Cancer
, 26
(1)
pp. 165-180.
10.1530/ERC-18-0134.
Preview |
Text
Oncometabolite induced primary cilia loss in pheochromocytoma.pdf - Published Version Download (3MB) | Preview |
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.
| Type: | Article |
|---|---|
| Title: | Oncometabolite induced primary cilia loss in pheochromocytoma |
| Location: | England |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1530/ERC-18-0134 |
| Publisher version: | https://doi.org/10.1530/ERC-18-0134 |
| Language: | English |
| Additional information: | Copyright © 2019 The authors. This work is licensed under a Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/). |
| Keywords: | pheochromocytoma; primary cilia; hypoxia; succinate dehydrogenase; von Hippel–Lindau protein |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > UCL BEAMS UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences UCL > Provost and Vice Provost Offices > UCL BEAMS > Faculty of Maths and Physical Sciences > Dept of Statistical Science |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10118995 |
Archive Staff Only
 |
View Item |
