Acetylation of EGF receptor contributes to tumor cell resistance to histone deacetylase inhibitors

Abstract

Alteration of epidermal growth factor receptor (EGFR) is involved in various human cancers and has been intensively investigated. A plethora of evidence demonstrates that posttranslational modifications of EGFR play a pivotal role in controlling its function and metabolism. Here, we show that EGFR can be acetylated by CREB binding protein (CBP) acetyltransferase. Interestingly, EGFR acetylation affects its tyrosine phosphorylation, which may contribute to cancer cell resistance to histone deacetylase inhibitors (HDACIs). Since there is an increasing interest in using HDACIs to treat various cancers in the clinic, our current study provides insights and rationale for selecting effective therapeutic regimen. Consistent with the previous reports, we also show that HDACI combined with EGFR inhibitors achieves better therapeutic outcomes and provides a molecular rationale for the enhanced effect of combination therapy. Our results unveil a critical role of EGFR acetylation that regulates EGFR function, which may have an important clinical implication.

4-(1-Ethyl-4-anisyl-imidazol-5-yl)-N-hydroxycinnamide – A new pleiotropic HDAC inhibitor targeting cancer cell signalling and cytoskeletal organisation

“…9B). This is a further indication for interference with EGFRtranslocation and -signalling playing a role in the antimigratory activity of these HDACi [20,71].…”

“…In contrast, HDAC6 is a cytoplasmic microtubule-associated deacetylase of alpha-tubulin and a moderator of microtubule dynamics and vesicle transport along microtubules [16][17][18][19][20]. Other non-histone substrates are the epidermal growth factor receptor (EGFR), [20,21] the transcription factor beta-catenin, [22] STAT1/3 (signal transducers and activators of transcription), [23] and angiogenesis-relevant proteins such as the vascular endothelial growth factor receptor (VEGFR), hypoxia inducible factor-1alpha (HIF-1alpha), and cortactin, a promotor of F-actin rearrangement [24][25][26][27].…”

Histone Deacetylase Inhibitors Resensitize EGFR/EGFRvIII-Overexpressing, Erlotinib-Resistant Glioblastoma Cells to Tyrosine Kinase Inhibition

“…One possible explanation for the failure of HDACi as single agents might be that HDACi have been described as transiently activating EGFR [40,41], which might also account for the slight increase in migration we observed for HDACi-only treated BS153 and DK-MG cells (Fig. 3).…”

Protein acetylation mechanisms in the regulation of insulin and insulin-like growth factor 1 signalling

“…Whether lysine acetylation may affect IGF-1 receptor activity has not been investigated. However, acetylation of the epidermal growth factor (EGF) receptor has been associated to enhanced EGF receptor tyrosine phosphorylation and oncogenic potential in the A431 tumour cell line, providing initial evidence for the functional relevance of acetylation as regulatory mechanism of receptor tyrosine kinases (Song et al, 2011).…”