Induction of c-Cbl contributes to anti-cancer effects of HDAC inhibitor in lung cancer
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Tzu-Tang Wei1,*, Yu-Chin Lin1,2,*, Pei-Hua Lin1, Jin-Yuan Shih3, Chia-Wei Chou1, Wei-Jan Huang4, Yu-Chih Yang5, Pei-Wen Hsiao5 and Ching-Chow Chen1
1 Department of Pharmacology, College of Medicine, National Taiwan University, Taipei, Taiwan
2 Department of Internal Medicine, Far-Eastern Memorial Hospital, New Taipei, Taiwan
3 Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
4 Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei, Taiwan
5 Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan
* These authors contributed equally to this work
Ching-Chow Chen, email:
Keywords: c-Cbl, EGFR, HDAC inhibitors, lung cancer
Received: November 28, 2014 Accepted: February 04, 2015 Published: March 08, 2015
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.
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