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Research ArticleCellular and Molecular

Downregulation of Ca2+-Activated Cl− Channel TMEM16A by the Inhibition of Histone Deacetylase in TMEM16A-Expressing Cancer Cells

Sayo Matsuba, Satomi Niwa, Katsuhiko Muraki, Saki Kanatsuka, Yurika Nakazono, Noriyuki Hatano, Masanori Fujii, Peng Zhan, Takayoshi Suzuki and Susumu Ohya
Journal of Pharmacology and Experimental Therapeutics December 2014, 351 (3) 510-518; DOI: https://doi.org/10.1124/jpet.114.217315
Sayo Matsuba
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.)
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Satomi Niwa
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.)
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Katsuhiko Muraki
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.)
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Saki Kanatsuka
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.)
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Yurika Nakazono
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.)
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Noriyuki Hatano
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.)
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Masanori Fujii
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.)
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Peng Zhan
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.)
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Takayoshi Suzuki
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.)
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Susumu Ohya
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.)
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Abstract

The Ca2+-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.

Footnotes

    • Received June 5, 2014.
    • Accepted September 17, 2014.
  • This work was supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (No. 25460111); a research grant from the Promotion and Mutual Aid Cooperation for Private Schools of Japan (Kyoto Pharmaceutical University and Aichi-Gakuin University); Mochida Memorial Foundation for Medical and Pharmaceutical Research; and Uehara Memorial Foundation (to S.O.).

  • dx.doi.org/10.1124/jpet.114.217315.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2014 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 351 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 351, Issue 3
1 Dec 2014
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Research ArticleCellular and Molecular

Downregulation of TMEM16A by HDAC3 Inhibition

Sayo Matsuba, Satomi Niwa, Katsuhiko Muraki, Saki Kanatsuka, Yurika Nakazono, Noriyuki Hatano, Masanori Fujii, Peng Zhan, Takayoshi Suzuki and Susumu Ohya
Journal of Pharmacology and Experimental Therapeutics December 1, 2014, 351 (3) 510-518; DOI: https://doi.org/10.1124/jpet.114.217315

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Research ArticleCellular and Molecular

Downregulation of TMEM16A by HDAC3 Inhibition

Sayo Matsuba, Satomi Niwa, Katsuhiko Muraki, Saki Kanatsuka, Yurika Nakazono, Noriyuki Hatano, Masanori Fujii, Peng Zhan, Takayoshi Suzuki and Susumu Ohya
Journal of Pharmacology and Experimental Therapeutics December 1, 2014, 351 (3) 510-518; DOI: https://doi.org/10.1124/jpet.114.217315
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