Downregulation of the Ca2+‐activated K+ channel KCa3.1 by histone deacetylase inhibition in human breast cancer cells

• Published in: Pharmacology research & perspectives Vol. 4; no. 2
• Main Authors: Ohya, Susumu, Kanatsuka, Saki, Hatano, Noriyuki, Kito, Hiroaki, Matsui, Azusa, Fujimoto, Mayu, Matsuba, Sayo, Niwa, Satomi, Zhan, Peng, Suzuki, Takayoshi, Muraki, Katsuhiko
• Format: Journal Article
• Language: English; Japanese
• Published: 01-04-2016
• Subjects: Breast cancer; Ca2+‐activated K+ channel; histone deacetylase inhibitor; vorinostat
• ISSN: 2052-1707; 2052-1707
• DOI: 10.1002/prp2.228

The intermediate‐conductance Ca2+‐activated K+ channel KCa3.1 is involved in the promotion of tumor growth and metastasis, and is a potential therapeutic target and biomarker for cancer. Histone deacetylase inhibitors (HDACis) have considerable potential for cancer therapy, however, the effects of HDACis on ion channel expression have not yet been investigated in detail. The results of this study showed a significant decrease in KCa3.1 transcription by HDAC inhibition in the human breast cancer cell line YMB‐1, which functionally expresses KCa3.1. A treatment with the clinically available, class I, II, and IV HDAC inhibitor, vorinostat significantly downregulated KCa3.1 transcription in a concentration‐dependent manner, and the plasmalemmal expression of the KCa3.1 protein and its functional activity were correspondingly decreased. Pharmacological and siRNA‐based HDAC inhibition both revealed the involvement of HDAC2 and HDAC3 in KCa3.1 transcription through the same mechanism. The downregulation of KCa3.1 in YMB‐1 was not due to the upregulation of the repressor element‐1 silencing transcription factor, REST and the insulin‐like growth factor‐binding protein 5, IGFBP5. The significant decrease in KCa3.1 transcription by HDAC inhibition was also observed in the KCa3.1‐expressing human prostate cancer cell line, PC‐3. These results suggest that vorinostat and the selective HDACis for HDAC2 and/or HDAC3 are effective drug candidates for KCa3.1‐overexpressing cancers.