The Ca2+-activated Cl- channel TMEM16A (also known as ANO1 or DOG1) plays an important role in facilitating cell growth and metastasis of TMEM16A-expressing cancer cells. Histone deacetylase HDAC inhibitors (HDACis) are useful agents for cancer therapy, but, it remains unclear whether ion channels are epigenetically regulated by HDACis. Utilizing real-time PCR, Western blot and whole-cell patch clamp assays, we found a significant decrease in TMEM16A expression and its functional activity induced by 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. Pharmacological blockade of HDAC3 by 1 μM T247, a HDAC3-selective HDACi elicited a large decrease in TMEM16A expression (~70 %) and functional activity (> 90 %) in both cell types, and pharmacological blockade of HDAC2 by AATB (300 nM) elicited partial inhibition of TMEM16A expression (~40 %) in both. Pharmacological blockade of HDAC1 or HDAC6 did not elicit any significant change in TMEM16A expression, respectively. In addition, siRNA-induced inhibition of HDAC3 elicited a large decrease in TMEM16A transcript in both cell types. Taken together, in malignancies with a frequent gene amplification of TMEM16A, HDAC3 inhibition is suggested to exert suppressive effects on cancer cell viability via a downregulation of TMEM16A.
- The American Society for Pharmacology and Experimental Therapeutics