The renal lineage factor PAX8 controls oncogenic signalling in kidney cancer
Autor: | Patel, Saroor A, Hirosue, Shoko, Rodrigues, Paulo, Vojtasova, Erika, Richardson, Emma K, Ge, Jianfeng, Syafruddin, Saiful E, Speed, Alyson, Papachristou, Eva, Baker, David, Clarke, David, Purvis, Stephenie, Wesolowski, Ludovic, Dyas, Anna, Castillon, Leticia, Caraffini, Veronica, Bihary, Dóra, Yong, Cissy, Harrison, David J, Stewart, Grant, Machiela, Mitchell J, Purdue, Mark P, Chanock, Stephen J, Warren, Anne, Samarajiwa, Shamith A, Carroll, Jason, Vanharanta, Sakari |
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Přispěvatelé: | Hirosue, Shoko [0000-0003-1287-471X], Vojtasova, Erika [0000-0001-9255-8551], Papachristou, Eva [0000-0002-5835-2055], Harrison, David J [0000-0001-9041-9988], Stewart, Grant [0000-0003-3188-9140], Machiela, Mitchell J [0000-0001-6538-9705], Chanock, Stephen J [0000-0002-2324-3393], Warren, Anne [0000-0002-1170-7867], Samarajiwa, Shamith A [0000-0003-1046-0601], Carroll, Jason [0000-0003-3643-0080], Vanharanta, Sakari [0000-0001-5619-7963], Apollo - University of Cambridge Repository, University of St Andrews. School of Medicine, University of St Andrews. Sir James Mackenzie Institute for Early Diagnosis, University of St Andrews. Cellular Medicine Division, CAN-PRO - Translational Cancer Medicine Program, Department of Physiology, Faculty of Medicine, University of Helsinki, Papachristou, Evangelia K [0000-0002-5835-2055], Stewart, Grant D [0000-0003-3188-9140], Warren, Anne Y [0000-0002-1170-7867], Carroll, Jason S [0000-0003-3643-0080] |
Rok vydání: | 2022 |
Předmět: |
82/29
PROMOTES Carcinogenesis 45/41 692/699/67/589/1588/1351 45/43 SUSCEPTIBILITY Kidney 13 59/5 59 BINDING Basic Helix-Loop-Helix Transcription Factors Cyclin D1 SPECIFICITY CYCLIN D1 64 Multidisciplinary Kidney Neoplasms Multidisciplinary Sciences Gene Expression Regulation Neoplastic 38/32 13/31 TARGET Von Hippel-Lindau Tumor Suppressor Protein 38/35 Science & Technology - Other Topics 38/39 64/60 631/67/70 Signal Transduction 3122 Cancers 13/106 QH426 Genetics 631/67/69 Article 38/91 RC0254 ENHANCER Proto-Oncogene Proteins c-myc 82/80 PAX8 Transcription Factor SDG 3 - Good Health and Well-being 38/89 631/208/200 HIF Humans QH426 Carcinoma Renal Cell Alleles 38/109 42 Science & Technology 45 RC0254 Neoplasms. Tumors. Oncology (including Cancer) 82/58 DAS 45/15 GENE Mutation 631/208/191 |
DOI: | 10.17863/cam.86051 |
Popis: | 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). |
Databáze: | OpenAIRE |
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