Lung cancer accounts for the largest number of cancer related deaths worldwide. Patients are either diagnosed with non-small cell lung cancer (NSCLC) or small cell lung cancer. NSCLC patients have poor prognostic outcomes with only a 15% five-year survival. The two most common NSCLC subtypes are lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). LUSC patients have a poorer clinical outcome due to the lack of targeted therapies. Hence, understanding the drivers of this disease will improve clinical outcome for patients.
We report here the identification of the transcriptional regulator BCL11A as a LUSC oncogene. We show that BCL11A knockdown in LUSC cell lines significantly reduced xenograft tumour growth and knocking out Bcl11a in primary tracheospheres abolished spheroid growth. In contrast, in vivo overexpression of BCL11A in the mouse airways led to the thickening of the airways and the development of hyperplastic lesions. In addition, BCL11A overexpression in primary tracheospheres led to the development of solid, disorganised organoids with squamous maintenance. At the molecular level we show that BCL11A is a target of SOX2 and that BCL11A is required for maintaining the SOX2-mediated oncogenicity in LUSC cell lines. Furthermore, we use ChIP-seq to show that BCL11A and SOX2 regulate the expression of several genes including the transcriptional and epigenetic regulators SETD8 and SKIL, which were both overexpressed in LUSC cell lines (n=5) in comparison to LUAD cell lines (n=6). Interestingly, SETD8 knockdown led to a growth arrest in 3D colony and xenograft assays selectively in LUSC cells but not in LUAD cells. Finally, SETD8 inhibition using compound NSC663284 demonstrated selective sensitization in LUSC cells in vitro.
In conclusion, our results describe an oncogenic role for BCL11A in LUSC and provide a potential future framework for tackling the unmet clinical need for LUSC patients.