Patients diagnosed with lung squamous cell carcinoma (LUSC) have limited targeted therapeutic options. We report here the identification and characterisation of the transcriptional regulator, BCL11A, as a LUSC oncogene. Analysis of cancer genomics datasets revealed BCL11A to be upregulated in LUSC but not in lung adenocarcinoma (LUAD). We demonstrated that knockdown of BCL11A in LUSC cell lines abolished xenograft tumour growth and its overexpression in vivo led to lung airway hyperplasia and the development of reserve cell hyperplastic lesions. In addition, deletion of Bcl11a in the tracheal basal cells abolished the development of tracheosphere organoids while its overexpression led to solid tracheospheres with a squamous phenotype. At the molecular level we found BCL11A to be a target of SOX2 and we show that it is required for the oncogenic role of SOX2 in LUSC. Furthermore, we showed that BCL11A and SOX2 interact at the protein level and that they regulate the expression of several transcription factors, including SETD8, SKIL and TBX2. We demonstrate that shRNA-mediated or pharmacological-mediated inhibition of SETD8 selectively affects in vitro and xenograft growth of LUSC cells in comparison to LUAD. Collectively, our study indicates that BCL11A is integral to LUSC pathology and that the disruption of the BCL11A-SOX2 transcriptional program could provide a future framework for the development of targeted therapeutics.
