Casitas B-Lineage Lymphoma-3 Is An Epigenetically Regulated Gene Whose Knockdown Induces Mesenchymal To Epithelial Transition And Enhances Erlotinib Sensitivity In Lung Cancer Cell Lines

Casitas B-lineage lymphoma (Cbl) proteins are E3 ubiquitin ligases and multifunctional adaptor proteins that are implicated in the regulation of signal transduction in various cell types and in response to different stimuli. Cbl-3 is a distinct member of this family of 3 genes that is specifically expressed in the epithelial lining of organs, particularly the bronchial airways, whose function, especially in cancer cells, is relatively unknown. Here we report that Cbl-3 expression and promoter CpG island DNA methylation differed profoundly in epithelial compared to mesenchymal-like lung cancer cells. 5-azacytidine treatment, as well as DNA methyltransferase-1 (DNMT1) KD (but not DNMT-3a or 3b) enhanced promoter demethylation and Cbl-3 gene expression. Knock down (KD) of Cbl-3 in mesenchymal-like lung cancer cell lines strongly enhanced EGFR expression and activated downstream pathways. As a result, cells that were normally resistant to erlotinib became greatly sensitized to drug treatment by Cbl-3 KD. Additionally, Cbl-3 KD inhibited cellular migration and increased cellular adhesion to the extra cellular matrix (ECM) as well as promoted cell-to-cell interaction through enhanced E-Cadherin and FAK expression. These alterations suggested a mesenchymal to epithelial transition (MET) conferred by Cbl-3 KD. Take together, this data provided new insights into Cbl-3 gene regulation and elucidated a potential role of Cbl-3 in EGFR signaling in the context of EMT in lung cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 207. doi:1538-7445.AM2012-207