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

Abstract

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...

Sporamin Intervention Altered the Gut Microbiome and Tumor Tissue Transcriptome in Mice Intraperitoneally Xenografted With the Human Colorectal Carcinoma LoVo Cells

“…The gene targets of ZBED6, including the Wnt, Hippo, TGF-β, EGF receptor, or PI3K pathway components, are all involved in CRC development [54]. BCL11A (B-cell lymphoma/leukemia 11A) also functions mainly as a transcriptional repressor [55] and down-regulation of BCL11A has been found mediating the resistance to radiotherapy in the treatment of CRC [56]. HSP90AA1 is closely related to the folding and assembly of many signaling molecules in the Ras/Raf/ERK/1/2 signaling pathway [57].…”