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Downregulation of Ca2+-activated Cl- channel TMEM16A by the inhibition of histone deacetylase in TMEM16A-expressing cancer cells.
J Pharmacol Exp Ther 2014; 351(3):510-8JP

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+Show Affiliations

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.).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.).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.).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.).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.).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.).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.).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.).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.).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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25232193

Citation

Matsuba, Sayo, et al. "Downregulation of Ca2+-activated Cl- Channel TMEM16A By the Inhibition of Histone Deacetylase in TMEM16A-expressing Cancer Cells." The Journal of Pharmacology and Experimental Therapeutics, vol. 351, no. 3, 2014, pp. 510-8.
Matsuba S, Niwa S, Muraki K, et al. Downregulation of Ca2+-activated Cl- channel TMEM16A by the inhibition of histone deacetylase in TMEM16A-expressing cancer cells. J Pharmacol Exp Ther. 2014;351(3):510-8.
Matsuba, S., Niwa, S., Muraki, K., Kanatsuka, S., Nakazono, Y., Hatano, N., ... Ohya, S. (2014). Downregulation of Ca2+-activated Cl- channel TMEM16A by the inhibition of histone deacetylase in TMEM16A-expressing cancer cells. The Journal of Pharmacology and Experimental Therapeutics, 351(3), pp. 510-8. doi:10.1124/jpet.114.217315.
Matsuba S, et al. Downregulation of Ca2+-activated Cl- Channel TMEM16A By the Inhibition of Histone Deacetylase in TMEM16A-expressing Cancer Cells. J Pharmacol Exp Ther. 2014;351(3):510-8. PubMed PMID: 25232193.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Downregulation of Ca2+-activated Cl- channel TMEM16A by the inhibition of histone deacetylase in TMEM16A-expressing cancer cells. AU - Matsuba,Sayo, AU - Niwa,Satomi, AU - Muraki,Katsuhiko, AU - Kanatsuka,Saki, AU - Nakazono,Yurika, AU - Hatano,Noriyuki, AU - Fujii,Masanori, AU - Zhan,Peng, AU - Suzuki,Takayoshi, AU - Ohya,Susumu, Y1 - 2014/09/17/ PY - 2014/9/19/entrez PY - 2014/9/19/pubmed PY - 2015/2/18/medline SP - 510 EP - 8 JF - The Journal of pharmacology and experimental therapeutics JO - J. Pharmacol. Exp. Ther. VL - 351 IS - 3 N2 - 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. SN - 1521-0103 UR - https://www.unboundmedicine.com/medline/citation/25232193/Downregulation_of_Ca2+-activated_Cl-_channel_TMEM16A_by_the_inhibition_of_histone_deacetylase_in_TMEM16A-expressing_cancer_cells L2 - http://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=25232193 DB - PRIME DP - Unbound Medicine ER -