Elevation of Histone deacetylase mediates lapatinib-induced cell mobility of triple-negative breast cancer cells through COX-2 overexpression
Wei-Chien Huang1,2,3
1Graduate Institute of Cancer Biology, China Medical University, 2The Ph.D. program for Cancer
Biology and Drug Discovery, China Medical University, Taichung 404, Taiwan.
2Center for Molecular Medicine, China Medical University Hospital, Taichung 404, Taiwan.
Abstract: Background
To broaden its clinical use, the dual EGFR/HER2 tyrosine kinase inhibitor lapatinib was tested in triple-negative breast cancer (TNBC) according to its anti-EGFR activity, but unfortunately has been shown to worsen the progression-free survival rate. Our previous study further explored that lapatinib renders TNBC cells more metastatic via increasing COX-2 expression. However, the molecular mechanism underlying the induction of COX-2 expression by lapatinib remains unclear.
Observations
Here, we showed that up-regulation of histone deacetylases (HDACs), accompanying with the deacetylation of histone H3K9 and H2BK5, were found in the lapatinib-treated TNBC cells. Treatment with HDAC inhibitors (SAHA and TSA) dramatically reduced lapatinib-mediated cell migration and invasion through down-regulation of COX-2 expression transcriptionally. Both activations of AP-1 and NF-κB were observed and mediated the COX-2 gene expression in the lapatinib-treated TNBC cells. HDAC inhibition reduces AP-1 but not NF-κB activation, suggesting that elevation of HDACs mediates lapatinib-induced COX-2 transcription through an AP-1-dependent manner.
Conclusions
Taken together, our results revealed that alterations of HDACs expression are involved in lapatinib-induced COX-2 expression and migration of TNBC cells and that co-treatment with HDAC inhibitors may improve the anti-tumor activity of lapatinib.
