The renal lineage factor PAX8 controls oncogenic signalling in kidney cancer.
Patel, Saroor A
Richardson, Emma K
Syafruddin, Saiful E
Purdue, Mark P
Springer Science and Business Media LLC
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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
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.
Medical Research Council (MC_UU_12022/7 and MC_UU_12022/10) and Kidney Research UK (RP_033_20170303).
Medical Research Council (MC_UU_12022/7)
Cancer Research UK (C96/A25177)
Kidney Research UK (RP_033_20170303)
European Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (955951)
National Institute for Health Research (NIHRDH-IS-BRC-1215-20014)
External DOI: https://doi.org/10.1038/s41586-022-04809-8
This record's URL: https://www.repository.cam.ac.uk/handle/1810/336599
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