Distinct transcriptional programs of SOX2 in different types of small cell lung cancers

BACKGROUND: SOX2 is an oncogene in human small cell lung cancer (SCLC), an aggressive neuroendocrine (NE) tumor. However, the roles of SOX2 in SCLC remain unclear, and strategies to selectively target SOX2 in SCLC cells have not yet been established.METHODS: In this study, we performed chromatin immunoprecipitation-sequenceing and found that SOX2 directly binding to the promoter region of INSM1 in the ASCL1-positive classical subtype of SCLC cell lines. The expression of ASCL1, SOX2, and INSM1 was assessed by RNA-sequencing, western blotting and immunohistochemistry. RNA interference and CRISPR/Cas9 system were used to assess the role of SOX2 in SCLC. Precursor SCLC lesions were established in Trp53 (-/-); CCSPrtTA; tetOCre; floxedRb1; floxedHes1 mice.RESULTS: SOX2 is involved in NE differentiation and tumorigenesis in cooperation with ASCL1 in the classical subtype of SCLC cell lines. ASCL1 recruits SOX2, which promotes INSM1 expression. The precursor SCLC lesions in mice were positive for Ascl1, Sox2, and Insm1. In contrast, SOX2 targeted distinct genes, such as those related to the Hippo pathway, in ASCL1-negative, variant subtype SCLC.CONCLUSIONS: The present results support the importance of the ASCL1-SOX2 axis as a main subtype of SCLC, and suggest the therapeutic potential of targeting the ASCL1-SOX2 axis.