Academic Journal
HNF1A recruits KDM6A to activate differentiated acinar cell programs that suppress pancreatic cancer
| العنوان: | HNF1A recruits KDM6A to activate differentiated acinar cell programs that suppress pancreatic cancer |
|---|---|
| المؤلفون: | Kalisz, M, Bernardo, E, Beucher, A, Maestro, MA, Del Pozo, N, Millán, I, Haeberle, L, Schlensog, M, Safi, SA, Knoefel, WT, Grau, V, De Vas, M, Shpargel, KB, Vaquero, E, Magnuson, T, Ortega, S, Esposito, I, Real, FX, Ferrer, J |
| بيانات النشر: | EMBO Press |
| سنة النشر: | 2020 |
| المجموعة: | Imperial College London: Spiral |
| مصطلحات موضوعية: | HNF1A, KDM6A, non-classical PDAC, pancreas, pancreas differentiation, Developmental Biology, 06 Biological Sciences, 08 Information and Computing Sciences, 11 Medical and Health Sciences |
| جغرافية الموضوع: | England |
| الوصف: | Defects in transcriptional regulators of pancreatic exocrine differentiation have been implicated in pancreatic tumorigenesis, but the molecular mechanisms are poorly understood. The locus encoding the transcription factor HNF1A harbors susceptibility variants for pancreatic ductal adenocarcinoma (PDAC), while KDM6A, encoding Lysine-specific demethylase 6A, carries somatic mutations in PDAC. Here, we show that pancreas-specific Hnf1a null mutant transcriptomes phenocopy those of Kdm6a mutations, and both defects synergize with KrasG12D to cause PDAC with sarcomatoid features. We combine genetic, epigenomic, and biochemical studies to show that HNF1A recruits KDM6A to genomic binding sites in pancreatic acinar cells. This remodels the acinar enhancer landscape, activates differentiated acinar cell programs, and indirectly suppresses oncogenic and epithelial-mesenchymal transition genes. We also identify a subset of non-classical PDAC samples that exhibit the HNF1A/KDM6A-deficient molecular phenotype. These findings provide direct genetic evidence that HNF1A deficiency promotes PDAC. They also connect the tumor-suppressive role of KDM6A deficiency with a cell-specific molecular mechanism that underlies PDAC subtype definition. |
| نوع الوثيقة: | article in journal/newspaper |
| اللغة: | English |
| تدمد: | 0261-4189 |
| Relation: | The EMBO Journal; http://hdl.handle.net/10044/1/79230 |
| DOI: | 10.15252/embj.2019102808 |
| الاتاحة: | http://hdl.handle.net/10044/1/79230 https://doi.org/10.15252/embj.2019102808 |
| Rights: | © 2020 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
| رقم الانضمام: | edsbas.FE115241 |
| قاعدة البيانات: | BASE |
Full Text Finder | تدمد: | 02614189 |
|---|---|
| DOI: | 10.15252/embj.2019102808 |