ODP558 Steroid Receptor Coactivators Promote Non-Small Cell Lung Cancer Tumorigenesis by Inhibiting Differentiation Factors, C/EBPα and NF-κB

The steroid receptor coactivator (SRC) family comprises three members, SRC-1 (NCOA1), SRC-2 (NCOA2), and SRC-3 (NCOA3). These SRC family members modulate diverse gene expression programs both by nuclear receptors and other transcription factors to drive physiological and pathophysiological processes. Notably, SRC-1, -2 and -3 also were found to be involved in different aspects of tumorigenesis. SRC-1 and SRC-3 overexpression has been observed in endometrial, ovarian, prostate, colorectal, gastric, lung, pancreatic and liver cancers. SRC-2 expression is elevated in patients with metastatic prostate cancer. This suggests that SRC family members are involved in signaling pathways critical for cancer cell proliferation and tumorigenesis. In the present study, we have begun to elucidate the mechanisms by which SRC members play a role in non-small cell lung cancer (NSCLC). We used the potent small-molecule SRC inhibitor, SI-2, which significantly impedes primary tumor growth in a breast cancer mouse model [1]. SI-2 selectively reduces cellular protein levels of SRC-1, SRC-2 and SRC-3 post transcriptionally. We observed that treatment of the NSCLC lines A549 and H1299 with SI-2 significantly induced protein expression of CCAAT/enhancer-binding protein-α (C/EBPα). C/EBPα is a basic leucine zipper transcription factor that is highly expressed in differentiated fetal lung epithelial cells, where it controls differentiation-dependent gene expression and inhibits cell proliferation. C/EBPα was found to be inactivated in various types of cancers, providing evidence for a possible tumor suppressor function of the C/EBPα (CEBPA) gene. We found that activation of C/EBPα in SI-2 treated NSCLC (A549 and H1299) was associated with a decline in the levels of histone deacetylases, HDAC-2 and-4. This suggests that inhibiting SRC family members in lung cancer cells causes reactivation of the epigenetically suppressed CEBPA gene by inhibiting histone deacetylase expression. We also observed that SI-2 increased expression of nuclear factor-κB (NF-κB) p65 protein in both A549 and H1299 cells. Previously, we found that NF-κB activates signaling pathways leading to enhanced fetal lung epithelial cell differentiation by decreasing HDAC-2 and -4 expression and binding to promoters of differentiation-inducing genes. Overall, we speculate that the SRC inhibitor, SI-2, blocks NSCLC proliferation and tumorigenesis by enhancing histone acetylation and transcriptional activation of putative tumor suppressors, C/EBPα and NF-κB, to increase lung epithelial cell differentiation. References1. Song, X., et al., Development of potent small-molecule inhibitors to drug the undruggable steroid receptor coactivator-3. Proceedings of the National Academy of Sciences, 2016. 113(18): p. 4970-4975. Presentation: No date and time listed