title: Downregulation of the Ca(2+)-activated K(+) channel KC a3.1 by histone deacetylase inhibition in human breast cancer cells.
abstract: The intermediate-conductance Ca(2+)-activated K(+) channel KC a3.1 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 KC a3.1 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 KC a3.1 transcription in a concentration-dependent manner, and the plasmalemmal expression of the KC a3.1 protein and its functional activity were correspondingly decreased. Pharmacological and siRNA-based HDAC inhibition both revealed the involvement of HDAC2 and HDAC3 in KC a3.1 transcription through the same mechanism. The downregulation of KC a3.1 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 KC a3.1 transcription by HDAC inhibition was also observed in the KC a3.1-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 KC a3.1-overexpressing cancers.
authors.affiliation: Department of Pharmacology Division of Pathological Sciences Kyoto Pharmaceutical University Kyoto 607-8414 Japan.
authors.forename: Susumu
authors.initials: S
authors.lastname: Ohya
authors.affiliation: Department of Pharmacology Division of Pathological Sciences Kyoto Pharmaceutical University Kyoto 607-8414 Japan.
authors.forename: Saki
authors.initials: S
authors.lastname: Kanatsuka
authors.affiliation: Laboratory of Cellular Pharmacology School of Pharmacy Aichi-Gakuin University Nagoya 464-8650 Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Hatano
authors.affiliation: Department of Pharmacology Division of Pathological Sciences Kyoto Pharmaceutical University Kyoto 607-8414 Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kito
authors.affiliation: Department of Pharmacology Division of Pathological Sciences Kyoto Pharmaceutical University Kyoto 607-8414 Japan.
authors.forename: Azusa
authors.initials: A
authors.lastname: Matsui
authors.affiliation: Department of Pharmacology Division of Pathological Sciences Kyoto Pharmaceutical University Kyoto 607-8414 Japan.
authors.forename: Mayu
authors.initials: M
authors.lastname: Fujimoto
authors.affiliation: Department of Pharmacology Division of Pathological Sciences Kyoto Pharmaceutical University Kyoto 607-8414 Japan.
authors.forename: Sayo
authors.initials: S
authors.lastname: Matsuba
authors.affiliation: Department of Pharmacology Division of Pathological Sciences Kyoto Pharmaceutical University Kyoto 607-8414 Japan.
authors.forename: Satomi
authors.initials: S
authors.lastname: Niwa
authors.affiliation: Graduate School of Medical Science Kyoto Prefectural University of Medicine Kyoto 606-0823 Japan.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhan
authors.affiliation: Graduate School of Medical Science Kyoto Prefectural University of Medicine Kyoto 606-0823 Japan.
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Laboratory of Cellular Pharmacology School of Pharmacy Aichi-Gakuin University Nagoya 464-8650 Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Muraki
keywords: Breast cancer; Ca2+‐activated K+ channel; histone deacetylase inhibitor; vorinostat