Induction of c-Cbl contributes to anti-cancer effects of HDAC inhibitor in lung cancer

Oncotarget. 2015 May 20;6(14):12481-92. doi: 10.18632/oncotarget.3489.

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.

Keywords: EGFR; HDAC inhibitors; c-Cbl; lung cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Carcinoma, Non-Small-Cell Lung / metabolism*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation
  • Fluorescent Antibody Technique
  • Gene Knockdown Techniques
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Immunohistochemistry
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Microscopy, Confocal
  • Proto-Oncogene Proteins c-cbl / biosynthesis*
  • RNA, Small Interfering
  • Transfection
  • Xenograft Model Antitumor Assays

Substances

  • Histone Deacetylase Inhibitors
  • RNA, Small Interfering
  • Proto-Oncogene Proteins c-cbl
  • CBL protein, human