Abstract
Here we found loss of c-Cbl, an E3 ligase, expression in non-small cell lung cancer (NSCLC) compared with its adjacent normal tissue in patient specimens. HDAC inhibition by WJ or knockdown of HDAC 1, HDAC2, HDAC3 or HDAC6 all induced c-Cbl. Ectopic expression of c-Cbl induced decreased EGFR, inhibited growth in NSCLC cells. Knockdown of EGFR inhibited NSCLC growth. Mutation of EGFR at Y1045 decreased WJ-induced growth inhibition as well as in vivo anti-cancer effect and EGFR degradation mediated by WJ. Time-lapse confocal analysis showed co-localization of c-Cbl and EGFR after WJ treatment. Furthermore, WJ inhibited lung tumor growth through c-Cbl induction in orthotopic and tail vein injected models. C-Cbl up-regulation induced by HDACi is a potential strategy for NSCLC treatment.
Highlights
Casitas B-lineage lymphoma (c-Cbl) protein is an E3 ubiquitin ligase regulating intracellular signaling [1]
Since c-Cbl is a tumor suppressor in lung adenocarcinoma, we screened a series of small molecules and found that histone deacetylases (HDACs) inhibitor (HDACi) SAHA could induce c-Cbl expression (Supplementary Figure S1A and Figure 1C)
WJ-induced growth inhibition and apoptosis were reversed by the knockdown of c-Cbl (Figure 1D), indicating that c-Cbl played a role in HDACi-induced anti-cancer effect
Summary
Casitas B-lineage lymphoma (c-Cbl) protein is an E3 ubiquitin ligase regulating intracellular signaling [1]. Its dysfunction mutation has been reported to induce myeloid neoplasm while overexpression inhibits tumor growth in xenograft models [2, 3], implicating its tumor suppressive role. C-Cbl acts through E3 ubiquitin ligase activity to promote epidermal growth factor receptor (EGFR) internalization and lysosome degradation [1, 4]. Over-expression of EGFR is frequently found in epithelial cancers and correlated with clinical aggressiveness and poor outcome [5, 6], suggesting that targeting EGFR is an important strategy for cancer treatment. AntiEGFR monoclonal antibody and EGFR tyrosine kinase inhibitor (TKI) have already led to great success in head and neck, colorectal, and non-small cell lung cancers [79]
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