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BCL11A interacts with SOX2 to control the expression of epigenetic regulators in lung squamous carcinoma
journal contributionposted on 2020-08-27, 15:23 authored by Kyren A Lazarus, Fazal Hadi, Elisabetta Zambon, Karsten Bach, Maria-Francesca Santolla, Julie K Watson, Lucia L Correia, Madhumita Das, Rosemary Ugur, Sara Pensa, Lukas Becker, Lia S Campos, Graham Ladds, Pentao Liu, Gerard I Evan, Frank M McCaughan, John Le Quesne, Joo-Hyeon Lee, Dinis Calado, Walid T 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.
AnimalsCarcinoma, Squamous CellCarrier ProteinsCell Line, TumorCell ProliferationEpigenesis, GeneticGene Expression Regulation, NeoplasticGene Knockdown TechniquesGenetic LociHistone-Lysine N-MethyltransferaseHumansLungLung NeoplasmsMiceNuclear ProteinsOncogenesOrganoidsProtein BindingRepressor ProteinsSOXB1 Transcription FactorsCalado FC001057