Trichostatin A suppresses EGFR expression through induction of microRNA-7 in an HDAC-independent manner in lapatinib-treated cells.
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 may be a feasible approach to improve the anticancer efficiency of lapatinib-based therapy. Inhibition 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.
Division of Pulmonary and Critical Care Medicine, China Medical University and Hospital, Taichung 404, Taiwan ; Department of Internal Medicine, China Medical University and Hospital, Taichung 404, Taiwan ; School of Medicine, China Medical University, Taichung 404, Taiwan ; Department of Life Science, National Chung-Hsing University, Taichung 402, Taiwan.
Chih-Yen
0000-0002-8126-6171
CY
Tu
Division of Pulmonary and Critical Care Medicine, China Medical University and Hospital, Taichung 404, Taiwan ; Department of Internal Medicine, China Medical University and Hospital, Taichung 404, Taiwan ; Department of Respiratory Therapy, China Medical University, Taichung 404, Taiwan ; Graduate Institute of Clinical Medical Science, China Medical University, Taichung 404, Taiwan.
Chia-Hung
CH
Chen
Department of Internal Medicine, China Medical University and Hospital, Taichung 404, Taiwan ; Department of Respiratory Therapy, China Medical University, Taichung 404, Taiwan.
Te-Chun
TC
Hsia
Graduate Institute of Cancer Biology, China Medical University, Taichung 404, Taiwan.
Min-Hsiang
MH
Hsu
Center for Molecular Medicine, China Medical University and Hospital, Taichung 404, Taiwan.
Ya-Ling
YL
Wei
Department of Internal Medicine, China Medical University and Hospital, Taichung 404, Taiwan ; Graduate Institute of Cancer Biology, China Medical University, Taichung 404, Taiwan.
Meng-Chieh
MC
Yu
Center for Molecular Medicine, China Medical University and Hospital, Taichung 404, Taiwan ; Department of Pharmacology, College of Medicine, National Taiwan University, Taipei 106, Taiwan.
Wen-Shu
WS
Chen
Department of Biological Science and Technology, China Medical University, Taichung 404, Taiwan.
Ke-Wei
KW
Hsu
Section of Breast Surgery, China Medical University and Hospital, Taichung 404, Taiwan.
Ming-Hsin
MH
Yeh
School of Medicine, China Medical University, Taichung 404, Taiwan ; Department of Surgery, China Medical University and Hospital, Taichung 404, Taiwan.
Liang-Chih
LC
Liu
Department of Medical Research, E-Da Hospital, Kaohsiung 824, Taiwan ; Department of Biological Science & Technology, I-Shou University, Kaohsiung 824, Taiwan.
Yun-Ju
YJ
Chen
Graduate Institute of Cancer Biology, China Medical University, Taichung 404, Taiwan ; Center for Molecular Medicine, China Medical University and Hospital, Taichung 404, Taiwan ; The Ph.D. Program for Cancer Biology and Drug Discovery, China Medical University, Taichung 404, Taiwan ; Department of Biotechnology, Asia University, Taichung 413, Taiwan.
Wei-Chien
0000-0001-6467-8716
WC
Huang
D000970:Antineoplastic Agents / Q000494:pharmacology; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D006655:Histone Deacetylases / Q000235:genetics*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D000077341:Lapatinib; D035683:MicroRNAs / Q000235:genetics*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000235:genetics
D000970:Antineoplastic Agents; D066246:ErbB Receptors; D006655:Histone Deacetylases; D006877:Hydroxamic Acids; D000077341:Lapatinib; D035683:MicroRNAs; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D012333:RNA, Messenger; C549242:MIRN7-1 microRNA, human; C012589:trichostatin A; C512478:EGFR protein, human