Abstract 2868: SETDB1 accelerates non-small cell lung cancer (NSCLC) tumorigenesis through WNT signalling pathway

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Histone methylationderegulation leads to disruption of chromatin structure and gene expression pattern in many human cancers. Histone H3 lysine K9 methyltransferase, SETDB1 ( SET domain, bifurcated 1) is initially reported to control heterochromatin structure, repress gene expression and be essential in early embryogenesis. Studies have recently shown its involvement in boosting tumorigenesis in different kinds of human cancers, including lung cancer. However, the mechanism underlying its ability to promote tumorigenesis remains largely unknown. In our study, we sought to investigate the oncogenic role of SETDB1 in NSCLC. Our immunohistochemistry found that 72% out of 387-lung cancer cases stained positively for SETDB1, compared to 46% samples of normal bronchial epithelium (p<0.0001). Moreover, the percent positive cells and their intensity of positivity correlated with cancer grades. Ectopic expression of SETDB1 in NSCLC cell lines enhanced clonogenic growth in vitro and significantly enlarges tumor size in vivo; while depleting endogenous SETDB1 expression with shRNAs suppressed NSCLC cells proliferation and tumor formation. Analyzing the expression pattern of cells with forced expression of SETDB1 combined with TOP/FOP luciferase assay and western blotting showed that WNT/β-catenin signaling was activated upon overexpression of SETDB1, as well as upregulation of its downstream targets, c-Myc and Cyclin D1. ChIP assayshowed that SETDB1 binds to WNT relevant genes, such as APOE, IGFBP4, FZD1and LRP8 and upregulates their transcription, which is very distinct from its canonical suppressing function of H3K9 trimethylation. Interestingly, we also noted that SETDB1 was able to repress P53 expression, while diminishing P53 expression reciprocally enhanced SETDB1 expression. In summary, our study demonstrates that SETDB1 enhances NSCLC tumorigenesis through activating WNT/β-catenin signaling and repressing tumor suppressor P53. Our novel findings provide new insight into a non-canonical function of SETDB1 in activating gene expression, and suggest therapeutic benefit of targeting SETDB1 in NSCLC having high expression level of this protein. Citation Format: Qiaoyang Sun, Lingwen Ding, Jinfen Xiao, Lee Goodglick, David Chia, Vei Mah, Mohammad Alavi, NganDoan, Jonathan W. Said, Henry Yang, H.Phillip Koeffler. SETDB1 accelerates non-small cell lung cancer (NSCLC) tumorigenesis through WNT signalling pathway. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2868. doi:10.1158/1538-7445.AM2015-2868