The renal lineage factor PAX8 controls oncogenic signalling in kidney cancer.
Authors
Patel, Saroor A
Rodrigues, Paulo
Richardson, Emma K
Ge, Jianfeng
Syafruddin, Saiful E
Speed, Alyson
Baker, David
Clarke, David
Purvis, Stephenie
Wesolowski, Ludovic
Dyas, Anna
Castillon, Leticia
Caraffini, Veronica
Bihary, Dóra
Yong, Cissy
Purdue, Mark P
Publication Date
2022-06-08Journal Title
Nature
ISSN
0028-0836
Publisher
Springer Science and Business Media LLC
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Patel, S. A., Hirosue, S., Rodrigues, P., Vojtasova, E., Richardson, E. K., Ge, J., Syafruddin, S. E., et al. (2022). The renal lineage factor PAX8 controls oncogenic signalling in kidney cancer.. Nature https://doi.org/10.1038/s41586-022-04809-8
Abstract
Large-scale human genetic data1-3 have shown that cancer mutations display strong tissue-selectivity, but how this selectivity arises remains unclear. Here, using experimental models, functional genomics and analyses of patient samples, we demonstrate that the lineage transcription factor paired box 8 (PAX8) is required for oncogenic signalling by two common genetic alterations that cause clear cell renal cell carcinoma (ccRCC) in humans: the germline variant rs7948643 at 11q13.3 and somatic inactivation of the von Hippel-Lindau tumour suppressor (VHL)4-6. VHL loss, which is observed in about 90% of ccRCCs, can lead to hypoxia-inducible factor 2α (HIF2A) stabilization6,7. We show that HIF2A is preferentially recruited to PAX8-bound transcriptional enhancers, including a pro-tumorigenic cyclin D1 (CCND1) enhancer that is controlled by PAX8 and HIF2A. The ccRCC-protective allele C at rs7948643 inhibits PAX8 binding at this enhancer and downstream activation of CCND1 expression. Co-option of a PAX8-dependent physiological programme that supports the proliferation of normal renal epithelial cells is also required for MYC expression from the ccRCC metastasis-associated amplicons at 8q21.3-q24.3 (ref. 8). These results demonstrate that transcriptional lineage factors are essential for oncogenic signalling and that they mediate tissue-specific cancer risk associated with somatic and inherited genetic variants.
Sponsorship
Medical Research Council (MC_UU_12022/7 and MC_UU_12022/10) and Kidney Research UK (RP_033_20170303).
Funder references
Medical Research Council (MC_UU_12022/7)
Cancer Research UK (C96/A25177)
Kidney Research UK (RP_033_20170303)
MRC (MC_UU_12022/10)
European Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (955951)
National Institute for Health Research (NIHRDH-IS-BRC-1215-20014)
Identifiers
External DOI: https://doi.org/10.1038/s41586-022-04809-8
This record's URL: https://www.repository.cam.ac.uk/handle/1810/336599
Rights
Attribution 4.0 International (CC BY)
Licence URL: http://creativecommons.org/licenses/by/4.0/
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