Journal Article

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

Ladds, Graham, Lee, Joo-Hyeon, Pensa, Sara, Calado, Dinis, Le Quesne, John, Campos, Lia S., Ugur, Rosemary, Hadi, Fazal, McCaughan, Frank M., Correia, Lucia L., Becker, Lukas, Bach, Karsten, Santolla, Maria-Francesca, Khaled, Walid T., Das, Madhumita, Liu, Pentao, Watson, Julie K., Lazarus, Kyren A., Evan, Gerard I., Zambon, Elisabetta

2018

Overview

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. Amongst the non-small cell lung cancers, to date, lung squamous cell carcinoma remains the most challenging to treat. Here the authors report BCL11A as an important factor which together with SOX2 can drive lung squamous cell carcinoma development and highlight a potential novel therapeutic candidate for this devastating disease.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/106 / 38/109 / 38/15 / 49/88 / 631/67/1059/602 / 631/67/1612/1350 / 64/60 / 82/1 / 82/51 / 82/80 / Adenocarcinoma / Animals / Cancer therapies / Carcinoma, Squamous Cell - drug therapy / Carcinoma, Squamous Cell - genetics / Carrier Proteins - metabolism / Cell Line, Tumor / Cell Proliferation - genetics / Chemotherapy / Disruption / Drug development / Epigenesis, Genetic / Epigenetics / FDA approval / Gene expression / Gene Expression Regulation, Neoplastic / Gene Knockdown Techniques / Genetic Loci / Genomes / Histone-Lysine N-Methyltransferase - genetics / Histone-Lysine N-Methyltransferase - metabolism / Humanities and Social Sciences / Humans / Hyperplasia / Kinases / Lung - pathology / Lung cancer / Lung carcinoma / Lung Neoplasms - drug therapy / Lung Neoplasms - genetics / Lymphoma / Mice / multidisciplinary / Nuclear Proteins - metabolism / Oncogenes / Organoids - pathology / Pharmacology / Phenotypes / Protein Binding / Regulators / Repressor Proteins / Science / Science (multidisciplinary) / SOXB1 Transcription Factors - metabolism / Squamous cell carcinoma / Transcription factors / Tumors / Xenografts / Xenotransplantation