title: Downregulation of Ca2+-activated Cl- channel TMEM16A by the inhibition of histone deacetylase in TMEM16A-expressing cancer cells.
abstract: The Ca(2+)-activated Cl(-) channel transmembrane proteins with unknown function 16 A (TMEM16A; also known as anoctamin 1 or discovered on gastrointestinal stromal tumor 1) plays an important role in facilitating the cell growth and metastasis of TMEM16A-expressing cancer cells. Histone deacetylase (HDAC) inhibitors (HDACi) are useful agents for cancer therapy, but it remains unclear whether ion channels are epigenetically regulated by them. Using real-time polymerase chain reaction, Western blot analysis, and whole-cell patch-clamp assays, we found a significant decrease in TMEM16A expression and its functional activity was induced by the vorinostat, a pan-HDACi in TMEM16A-expressing human cancer cell lines, the prostatic cancer cell line PC-3, and the breast cancer cell line YMB-1. TMEM16A downregulation was not induced by the chemotherapy drug paclitaxel in either cell type. Pharmacologic blockade of HDAC3 by 1 μM T247 [N-(2-aminophenyl)-4-[1-(2-thiophen-3-ylethyl)-1H-[1],[2],[3]triazol-4-yl]benzamide], a HDAC3-selective HDACi, elicited a large decrease in TMEM16A expression and functional activity in both cell types, and pharmacologic blockade of HDAC2 by AATB [4-(acetylamino)-N-[2-amino-5-(2-thienyl)phenyl]-benzamide; 300 nM] elicited partial inhibition of TMEM16A expression (∼40%) in both. Pharmacologic blockade of HDAC1 or HDAC6 did not elicit any significant change in TMEM16A expression, respectively. In addition, inhibition of HDAC3 induced by small interfering RNA elicited a large decrease in TMEM16A transcripts in both cell types. Taken together, in malignancies with a frequent gene amplification of TMEM16A, HDAC3 inhibition may exert suppressive effects on cancer cell viability via downregulation of TMEM16A.
authors.affiliation: Department of Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto, Japan (S.M., S.N., S.K., Y.N., M.F., S.O.); Laboratory of Cellular Pharmacology, School of Pharmacy, Aichi-Gakuin University, Nagoya, Japan (K.M., N.H.); and Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan (P.Z., T.S.).
authors.forename: Sayo
authors.initials: S
authors.lastname: Matsuba
authors.affiliation: Department of Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto, Japan (S.M., S.N., S.K., Y.N., M.F., S.O.); Laboratory of Cellular Pharmacology, School of Pharmacy, Aichi-Gakuin University, Nagoya, Japan (K.M., N.H.); and Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan (P.Z., T.S.).
authors.forename: Satomi
authors.initials: S
authors.lastname: Niwa
authors.affiliation: Department of Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto, Japan (S.M., S.N., S.K., Y.N., M.F., S.O.); Laboratory of Cellular Pharmacology, School of Pharmacy, Aichi-Gakuin University, Nagoya, Japan (K.M., N.H.); and Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan (P.Z., T.S.).
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Muraki
authors.affiliation: Department of Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto, Japan (S.M., S.N., S.K., Y.N., M.F., S.O.); Laboratory of Cellular Pharmacology, School of Pharmacy, Aichi-Gakuin University, Nagoya, Japan (K.M., N.H.); and Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan (P.Z., T.S.).
authors.forename: Saki
authors.initials: S
authors.lastname: Kanatsuka
authors.affiliation: Department of Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto, Japan (S.M., S.N., S.K., Y.N., M.F., S.O.); Laboratory of Cellular Pharmacology, School of Pharmacy, Aichi-Gakuin University, Nagoya, Japan (K.M., N.H.); and Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan (P.Z., T.S.).
authors.forename: Yurika
authors.initials: Y
authors.lastname: Nakazono
authors.affiliation: Department of Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto, Japan (S.M., S.N., S.K., Y.N., M.F., S.O.); Laboratory of Cellular Pharmacology, School of Pharmacy, Aichi-Gakuin University, Nagoya, Japan (K.M., N.H.); and Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan (P.Z., T.S.).
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Hatano
authors.affiliation: Department of Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto, Japan (S.M., S.N., S.K., Y.N., M.F., S.O.); Laboratory of Cellular Pharmacology, School of Pharmacy, Aichi-Gakuin University, Nagoya, Japan (K.M., N.H.); and Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan (P.Z., T.S.).
authors.forename: Masanori
authors.initials: M
authors.lastname: Fujii
authors.affiliation: Department of Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto, Japan (S.M., S.N., S.K., Y.N., M.F., S.O.); Laboratory of Cellular Pharmacology, School of Pharmacy, Aichi-Gakuin University, Nagoya, Japan (K.M., N.H.); and Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan (P.Z., T.S.).
authors.forename: Peng
authors.initials: P
authors.lastname: Zhan
authors.affiliation: Department of Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto, Japan (S.M., S.N., S.K., Y.N., M.F., S.O.); Laboratory of Cellular Pharmacology, School of Pharmacy, Aichi-Gakuin University, Nagoya, Japan (K.M., N.H.); and Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan (P.Z., T.S.).
authors.forename: Takayoshi
authors.initials: T
authors.lastname: Suzuki
authors.affiliation: Department of Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto, Japan (S.M., S.N., S.K., Y.N., M.F., S.O.); Laboratory of Cellular Pharmacology, School of Pharmacy, Aichi-Gakuin University, Nagoya, Japan (K.M., N.H.); and Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan (P.Z., T.S.) sohya@mb.kyoto-phu.ac.jp.
authors.forename: Susumu
authors.initials: S
authors.lastname: Ohya
mesh_terms: D000075369:Anoctamin-1; D045744:Cell Line, Tumor; D018118:Chloride Channels / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D061986:MCF-7 Cells; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D000077337:Vorinostat
chemical_list: C476213:ANO1 protein, human; D000075369:Anoctamin-1; D018118:Chloride Channels; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D009363:Neoplasm Proteins; D000077337:Vorinostat