Trichostatin A Suppresses EGFR Expression through Induction of MicroRNA-7
in an HDAC-Independent Manner in Lapatinib-Treated Cells
Chih-Yen Tu, Chia-Hung Chen, Te-Chun Hsia, Min-Hsiang Hsu, Ya-Ling Wei, Meng-Chieh Yu, Wen-Shu Chen, Ke-Wei Hsu, Ming-Hsin Yeh, Liang-Chih Liu, Yun-Ju Chen, and Wei-Chien Huang
Lapatinib, a dual EGFR/HER2 tyrosine kinase inhibitor, has been shown to improve the survival rate of patients with advanced HER2-positive breast cancers. However, the off-target activity of lapatinib in inducing EGFR expression without tyrosine kinase activity was demonstrated to render HER2-negative breast cancer cells more metastatic, suggesting a limitation to the therapeutic effectiveness of this dual inhibitor in HER2-heterogeneous tumors. Therefore, targeting EGFR expression maybe a feasible approach to improve the anticancer efficiency of lapatinib-based therapy. Inhibiti on of HDAC has been previously reported to epigenetically suppress EGFR protein expression. In this study, however, our data indicated that treatment with HDAC inhibitors trichostatin A (TSA), but not suberoylanilide hydroxamic acid (SAHA) or HDAC siRNA, can attenuate both protein and mRNA expressions of EGFR in lapatinib-treated triple-negative breast cancer cells, suggesting that TSA may suppress EGFR expression independently of HDAC inhibition. Nevertheless, TSA reduced EGFR 3 UTR activity and induced the gene
expression of microRNA-7, a known EGFR-targeting microRNA.
Furthermore, treatment with microRNA-7 inhibitor attenuated TSA-mediated EGFR suppression. These results suggest that TSA induced microRNA-7 expression to downregulate EGFR expression in an HDAC-independent manner.
Center for Molecular Medicine, China Medical University and Hospital Graduate Institute of Cancer Biology, China Medical University
Department of Medical Research, E-Da Hospital, Kaohsiung 824, Taiwan
Department of Biological Science & Technology, I-Shou University, Kaohsiung 824, Taiwan Department of Biotechnology, Asia University, Taichung 413, Taiwan
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Figure 6 Figure 1 TSA but not SAHA suppressed lapatinib-induced EGFR expression.
HDAC3 and HDAC7 expressions were elevated to cause histone hypoacetylations in lapatinib-treated MDA-MB-231 cell.
Silence of HDACs did not affect EGFR expression in lapatinib-treated MDA-MB-231 cells.
Proteasomal or lysosomal protein degradations were not involved in TSA-induced EGFR downregulation.
TSA induced miR-7 to suppress EGFR expression.
Abstract
TSA suppressed the 3’UTR activity of EGFR mRNA.
Acknowledgments
This work was supported by Grants from E-Da Hospital (EDAHT100024, EDAHT100026), the National Science Council of Taiwan (NSC 102-2320-B-039-054-MY3, NSC 102-2320-B-039-052, NSC 101-2911-I-002-303, and NSC 101-2320-B-039-049 to W.C.H), China Medical University and Hospital (CMU102-S-12 to C.-Y. Tu), and the National Health Research Institutes of Taiwan (NHRI-EX103-10329BI to W.-C. Huang).
Our data uncovered a unique activity of TSA in inducing miR-7 expression. In distinction to its structural relative SAHA, TSA suppressed EGFR 3’UTR activity to attenuate its protein expression independently of HDAC inhibition in lapatinib-treated breast cancer cells. These results suggest a possible off-target activity of TSA in suppressing EGFR expression.
