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BCL11A interacts with SOX2 to control the expression of epigenetic regulators in lung squamous carcinoma.

Nat Commun. 2018 Aug 20;9(1):3327
Kyren A Lazarus 1 , Fazal Hadi 1 , Elisabetta Zambon 1 , Karsten Bach 1 , Maria-Francesca Santolla 2 , Julie K Watson 3 , Lucia L Correia 4 , Madhumita Das 5 , Rosemary Ugur 1 , Sara Pensa 1 , Lukas Becker 6 , Lia S Campos 7 , Graham Ladds 6 , Pentao Liu 7 , Gerard I Evan 4 , Frank M McCaughan 4 , John Le Quesne 8 , Joo-Hyeon Lee 3 , Dinis Calado 9 , Walid T Khaled 10
Kyren A Lazarus 1 , Fazal Hadi 1 , Elisabetta Zambon 1 , Karsten Bach 1 , Maria-Francesca Santolla 2 , Julie K Watson 3 , Lucia L Correia 4 , Madhumita Das 5 , Rosemary Ugur 1 , Sara Pensa 1 , Lukas Becker 6 , Lia S Campos 7 , Graham Ladds 6 , Pentao Liu 7 , Gerard I Evan 4 , Frank M McCaughan 4 , John Le Quesne 8 , Joo-Hyeon Lee 3 , Dinis Calado 9 , Walid T Khaled 10
+ et al

[No authors listed]

Author information
  • 1 Cambridge Cancer Centre, CB2 0XZ, Cambridge, UK.
  • 2 Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, 87036, Italy.
  • 3 WT-MRC Stem Cell Institute, University of Cambridge, Cambridge, CB2 0SZ, UK.
  • 4 Department of Biochemistry, University of Cambridge, Cambridge, CB2 1GA, UK.
  • 5 MRC Toxicology Unit, Lancaster Road, Leicester, LE1 7HB, UK.
  • 6 Department of Pharmacology, University of Cambridge, Cambridge, CB2 1PD, UK.
  • 7 Wellcome Trust Sanger Institute, Cambridge, CB10 1SA, UK.
  • 8 University Hospitals Leicester NHS trust, Leicester, LE1 5WW, UK.
  • 9 The Francis Crick Institute, London, NW1 1AT, UK.
  • 10 WT-MRC Stem Cell Institute, University of Cambridge, Cambridge, CB2 0SZ, UK. wtk22@cam.ac.uk.

摘要

Patients diagnosed with lung squamous cell carcinoma (LUSC) have limited targeted therapies. We report here the identification and characterisation of BCL11A, as a LUSC oncogene. Analysis of cancer genomics datasets revealed BCL11A to be upregulated in LUSC but not in lung adenocarcinoma (LUAD). Experimentally we demonstrate that non-physiological levels of BCL11A in vitro and in vivo promote squamous-like phenotypes, while its knockdown abolishes xenograft tumour formation. At the molecular level we found that BCL11A is transcriptionally regulated by SOX2 and is required for its oncogenic functions. Furthermore, we show that BCL11A and SOX2 regulate the expression of several transcription factors, including SETD8. We demonstrate that shRNA-mediated or pharmacological inhibition of SETD8 selectively inhibits LUSC growth. Collectively, our study indicates that BCL11A is integral to LUSC pathology and highlights the disruption of the BCL11A-SOX2 transcriptional programme as a novel candidate for drug development.

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