journal contribution posted on 11.07.2019, 10:58 by KA Lazarus, F Hadi, E Zambon, K Bach, M-F Santolla, JK Watson, LL Correia, M Das, R Ugur, S Pensa, L Becker, LS Campos, G Ladds, P Liu, G Evan, FM McCaughan, J Le Quesne, J-H Lee, D Calado, WT Khaled
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.
We would like to thank the staff at Sanger Institute, Research Service Facility (RSF) for their assistance. We would like to thank Dr. Catherine Wilson and Dr. Deborah Burkhart (Department of Biochemistry, Cambridge) for her help with the Adenovirus experiment. We would like to thank Dr. Emma Rawlins for helpful discussions and comments. We would like to thank Agnetta Lazarus and members of the WTK Lab for comments on the manuscript. G.L. was supported by the BBSRC (Grant BB/M00015X/2). F.H. is funded by a Gates foundation Studentship. E.Z is funded by an AstraZeneca Studentship, K.B. is funded by a CCC studentship R.U. is funded by a NC3Rs studentship. F.M. and L.L.C. were funded by a Wellcome Trust Intermediate Clinical Fellowship to F.M.M (WT097143MA).W.T.K. is funded by a CRUK Career Establishment Award (C47525/A17348), CRUK Small Molecule Drug Discovery Project Award (C47525/A25850), The Isaac Newton Trust Grant (16.38c), University of Cambridge and Magdalene College, Cambridge.
CitationNature Communications, 2018, 9, Article number: 3327
Author affiliation/Organisation/COLLEGE OF LIFE SCIENCES/School of Medicine/Cancer Research Centre
VersionVoR (Version of Record)
Published inNature Communications
PublisherNature Research (part of Springer Nature)
Source code will be available on request.
The Chipseq data is available from ArrayExpress (accession numbers: # E-MTAB-6958) . The authors declare that all remaining data supporting the findings of this study are available within the article and its Supplementary Information files or from the authors upon request.