Novel Transcriptional Targets of the SRY-HMG Box Transcription Factor SOX4 Link Its Expression to the Development of Small Cell Lung Cancer

• Published in: Cancer research (Chicago, Ill.) Vol. 72; no. 1; pp. 176 - 186
• Main Authors: CASTILLO, Sandra D, MATHEU, Ander, MARIANI, Niccolo, CARRETERO, Julian, LOPEZ-RIOS, Fernando, LOVELL-BADGE, Robin, SANCHEZ-CESPEDES, Montse
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 2012
• Subjects: Aging - genetics; Animals; Antineoplastic agents; Biological and medical sciences; Blotting, Western; Carcinoma, Small Cell - genetics; Carcinoma, Small Cell - pathology; Cell Line, Tumor; Chromatin Immunoprecipitation; Gene Expression; Humans; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Medical sciences; Mice; Pharmacology. Drug treatments; Pneumology; Promoter Regions, Genetic; Real-Time Polymerase Chain Reaction; SOXC Transcription Factors - genetics; SOXC Transcription Factors - metabolism; Transcription, Genetic; Tumors; Tumors of the respiratory system and mediastinum; Lung disease; Targeting; Nuclear protein HMG; Transcription; Respiratory disease; Lung cancer; Bonchopulmonary small cell carcinoma; Malignant tumor; Gene expression; Signal transduction; Target; Development; Bronchus disease; Transcription factor; Cancer; Testis-determining factor
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-11-3506

The HMG box transcription factor SOX4 involved in neuronal development is amplified and overexpressed in a subset of lung cancers, suggesting that it may be a driver oncogene. In this study, we sought to develop this hypothesis including by defining targets of SOX4 that may mediate its involvement in lung cancer. Ablating SOX4 expression in SOX4-amplified lung cancer cells revealed a gene expression signature that included genes involved in neuronal development such as PCDHB, MYB, RBP1, and TEAD2. Direct recruitment of SOX4 to gene promoters was associated with their upregulation upon ectopic overexpression of SOX4. We confirmed upregulation of the SOX4 expression signature in a panel of primary lung tumors, validating their specific response by a comparison using embryonic fibroblasts from Sox4-deficient mice. Interestingly, we found that small cell lung cancer (SCLC), a subtype of lung cancer with neuroendocrine characteristics, was generally characterized by high levels of SOX2, SOX4, and SOX11 along with the SOX4-specific gene expression signature identified. Taken together, our findings identify a functional role for SOX genes in SCLC, particularly for SOX4 and several novel targets defined in this study.