RESUMEN
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.
Asunto(s)
Carcinoma de Células Escamosas/genética , Proteínas Portadoras/metabolismo , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Neoplasias Pulmonares/genética , Proteínas Nucleares/metabolismo , Factores de Transcripción SOXB1/metabolismo , Animales , Carcinoma de Células Escamosas/tratamiento farmacológico , Línea Celular Tumoral , Proliferación Celular/genética , Técnicas de Silenciamiento del Gen , Sitios Genéticos , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Humanos , Pulmón/patología , Neoplasias Pulmonares/tratamiento farmacológico , Ratones , Oncogenes , Organoides/patología , Unión Proteica , Proteínas RepresorasRESUMEN
BACKGROUND: Diabetes is a complex progressive disease characterized by chronic hyperglycaemia and dyslipidaemia associated with endothelial dysfunction. Oxidized LDL (Ox-LDL) is elevated in diabetes and may contribute to endothelial dysfunction. The aim of this study was to relate the serum levels of Ox-LDL with endothelial dysfunction in streptozotocin (STZ)-diabetic rats and to further explore the changes in endothelial nitric oxide synthase (eNOS) and caveolin-1 (CAV-1) expression in primary aortic endothelial cells. METHODS: Diabetes was induced with a single intraperitoneal injection of STZ in male Wistar rats. During the hyperglycaemic diabetes state serum lipid markers, aortic relaxation and aortic endothelial cell eNOS and CAV-1 protein expressions were measured. RESULTS: Elevated serum Ox-LDL (STZ 1486 ± 78.1 pg/mL vs control 732.6 ± 160.6 pg/mL, P < .05) was associated with hyperglycaemia (STZ 29 ± 0.9 mmol/L vs control: 7.2 ± 0.2 mmol/L, P < .001) and hypertriglyceridaemia (STZ 9.0 ± 1.5 mmol/L vs control: 3.0 ± 0.3 mmol/L, P < .01) in diabetic rats. A significant reduction was observed in STZ-diabetic aortic endothelial cell eNOS and CAV-1 of 40% and 30%, respectively, accompanied by a compromised STZ-diabetic carbachol-induced vasodilation (STZ 29.6 ± 9.3% vs control 77.2 ± 2.5%, P < .001). CONCLUSIONS: The elevated serum Ox-LDL in hyperglycaemic STZ-diabetic rats may contribute to diabetic endothelial dysfunction, possibly through downregulation of endothelial CAV-1 and eNOS.
