PO-086 BCL11A interacts with SOX2 to control the expression of epigenetic regulators in lung squamous cell carcinoma

Introduction Lung cancer accounts for the highest rate of cancer related diagnosis and mortality worldwide. Small cell lung cancer and non-small cell lung cancer (NSCLC) make up the major subtypes of lung cancer. NSCLC patients only have a 15% five-year survival rate. The major subtypes of NSCLC are lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). LUSC accounts for more than 4 00 000 deaths each year and unlike LUAD there are limited targeted therapies. Therefore, a great deal of work still needs to be done to understand the drivers for this cancer. Material and methods shRNA was utilised to modulate the levels of BCL11A and SOX2 in LUSC cell lines. In vitro 3D colony assays and xenograft mouse models were employed to understand the role of BCL11A in driving LUSC tumorigenesis. To explore the role of BCL11A in vivo , a Cre-inducible BCL11A overexpression mouse model was used. To further investigate BCL11A in LUSC, a mouse tracheal basal cells organoid assay was employed. CHIP-seq, immunoprecipitation and immunoblotting assays were designed to dissect the mechanism by which BCL11A elicits its function in LUSC. Drug dose response assays were used to test the efficacy of SETD8 inhibitors and cisplatin on an array of lung cancer cell lines. Results and discussions Analysis of TCGA has revealed BCL11A to be upregulated in LUSC but not LUAD. Subsequently reducing BCL11A levels in LUSC cell lines results in diminished xenograft tumour growth. Inversely, its overexpression in vivo led to lung airway hyperplasia and the development of reserve cell hyperplastic lesions which is a precursor to squamous metaplasia. Moreover, deleting Bcl11a in mouse tracheal basal cells abolished the development of tracheosphere organoids while its overexpression led to solid tracheospheres expressing markers of squamous cells. 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 together they co-regulated the expression of several transcription factors. We demonstrate that pharmacological inhibition of SETD8, a gene co-regulated by BCL11A and SOX2, alone or in combination with cisplatin treatment, shows significant selectivity to LUSC in comparison to LUAD cells. Conclusion Collectively, these results indicate that the disruption of the BCL11A-SOX2 transcriptional program provides a future framework for the development of targeted therapeutic intervention for LUSC patients.