Downregulation of Ca2+-activated Cl- channel TMEM16A by the inhibition of histone deacetylase in TMEM16A-expressing cancer cells

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 (...

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Bibliographic Details
Published in:	The Journal of pharmacology and experimental therapeutics Vol. 351; no. 3; p. 510
Main Authors:	Matsuba, Sayo, Niwa, Satomi, Muraki, Katsuhiko, Kanatsuka, Saki, Nakazono, Yurika, Hatano, Noriyuki, Fujii, Masanori, Zhan, Peng, Suzuki, Takayoshi, Ohya, Susumu
Format:	Journal Article
Language:	English
Published:	United States 01-12-2014
Subjects:	Anoctamin-1 Cell Line, Tumor Chloride Channels - antagonists & inhibitors Chloride Channels - biosynthesis Down-Regulation - drug effects Down-Regulation - physiology Gene Expression Regulation, Neoplastic Histone Deacetylase Inhibitors - pharmacology Humans Hydroxamic Acids - pharmacology MCF-7 Cells Neoplasm Proteins - antagonists & inhibitors Neoplasm Proteins - biosynthesis
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Summary:	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.
ISSN:	1521-0103
DOI:	10.1124/jpet.114.217315