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.

25Patients diagnosed with lung squamous cell carcinoma (LUSC) have limited targeted 26 therapeutic options. We report here the identification and characterisation of the 27 transcriptional regulator, BCL11A, as a LUSC oncogene. Analysis of cancer genomics 28 datasets revealed BCL11A to be upregulated in LUSC but not lung adenocarcinoma 29 (LUAD). We demonstrated that knockdown of BCL11A in LUSC cell lines abolished 30 xenograft tumour growth and its overexpression in vivo led to lung airway hyperplasia 31 and the development of reserve cell hyperplastic lesions. In addition, deletion of Bcl11a 32 in the tracheal basal cells abolished the development of tracheosphere organoids while 33 its overexpression led to solid tracheospheres with a squamous phenotype. At the 34 molecular level we found BCL11A to be a target of SOX2 and we show that it is 35 required for the oncogenic role of SOX2 in LUSC. Furthermore, we showed that 36 BCL11A and SOX2 interact at the protein level and that together they co-regulated the 37 expression of several transcription factors. We demonstrate that pharmacological 38 inhibition of SETD8, a gene co-regulated by BCL11A and SOX2, alone or in 39 combination with cisplatin treatment, shows significant selectivity to LUSC in 40 comparison to LUAD cells. Collectively, these results indicate that the disruption of the 41 BCL11A-SOX2 transcriptional program provides a future framework for the 42 development of targeted therapeutic intervention for LUSC patients. 43 44 45 3 Main 46 Lung cancer accounts for the highest rate of cancer related diagnosis and mortality 47 worldwide 1 . Broadly, there are two major types of lung cancer; small cell lung cancer 48 (SCLC) accounting for 15% of the cases and non-small cell lung cancer (NSCLC) 49 accounting for 85% of cases 1 . NSCLC patients have a poor outcome in the clinic with 50 only 15% of patients surviving five years or more 2 . At present NSCLC is defined histo-51 pathologically in the clinic into four broad categories: lung adenocarcinoma (LUAD), 52 lung squamous cell carcinoma (LUSC), large cell carcinoma and undifferentiated non-53 small cell lung cancer. LUAD and LUSC are the most common types of NSCLC (90% 54 of cases). LUSC accounts for more than 400,000 deaths worldwide each year 3 and 55 unlike LUAD there are limited targeted therapies available for LUSC. Platinum-based 56 chemotherapy remains the first-line treatment for LUSC and although the recent FDA 57 approval of Necitumumab in combination with platinum-based chemotherapy for 58 metastatic LUSC has shown positive signs, a great deal of work still needs to be done in 59 this field 4 . 60 61At the cellular level, LUAD tends to originate from the secretory epithelial cells in the 62 lung while LUSC usually originates from basal cells in the main and central airways 2 . 63At the molecular level LUAD is known to harbour mutations in epidermal growth factor 64 receptor (EGFR), V-Ki-Ras2 Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) 65 and Anaplastic Lymphoma Receptor Tyrosine Kin...

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