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.

The single channel current of intermediate conductance Ca2 +-activated K+ channel (IK channel) was measured in mouse urinary bladder myocytes (MBM), and the molecular basis of the channel was suggested to be the SK4 subtype by RT-PCR. Among Ca2+-activated K+ channel subtypes (SK2, SK3, SK4 and BK), the mRNAs of SK4 and BK were predominantly expressed in MBM. IK channel currents recorded from MBM showed: 38.7 pS slope conductance under symmetrical 140 mM K+ conditions, Ca2+-dependent activation, and blockade by charybdotoxin and econazole. These results strongly suggest that SK4 encodes IK channels in MBM.

The intermediate-conductance Ca²⁺-activated K⁺channel K_Ca3.1/KCNN4 plays an important role in the modulation of Ca²⁺signaling through the control of the membrane potential in T lymphocytes. Here, we study the involvement of K_Ca3.1 in the enlargement of the mesenteric lymph nodes (MLNs) in a mouse model of inflammatory bowel disease (IBD). The mouse model of IBD was prepared by exposing male C57BL/6J mice to 5% dextran sulfate sodium for 7 days. Inflammation-induced changes in K_Ca3.1 activity and the expressions of K_Ca3.1 and its regulators in MLN CD4⁺T lymphocytes were monitored by real-time PCR, Western blot, voltage-sensitive dye imaging, patch-clamp, and flow cytometric analyses. Concomitant with an upregulation of K_Ca3.1a and nucleoside diphosphate kinase B (NDPK-B), a positive K_Ca3.1 regulator, an increase in K_Ca3.1 activity was observed in MLN CD4⁺T lymphocytes in the IBD model. Pharmacological blockade of K_Ca3.1 elicited the following results: 1) a significant decrease in IBD disease severity, as assessed by diarrhea, visible fecal blood, inflammation, and crypt damage of the colon and MLN enlargement compared with control mice, and 2) the restoration of the expression levels of K_Ca3.1a, NDPK-B, and Th1 cytokines in IBD model MLN CD4⁺T lymphocytes. These findings suggest that the increase in K_Ca3.1 activity induced by the upregulation of K_Ca3.1a and NDPK-B may be involved in the pathogenesis of IBD by mediating the enhancement of the proliferative response in MLN CD4⁺T lymphocyte and, therefore, that the pharmacological blockade of K_Ca3.1 may decrease the risk of IBD.

The intermediate‐conductance Ca²⁺‐activated K⁺ channel K_Ca3.1 is involved in the promotion of tumor growth and metastasis, and is a potential therapeutic target and biomarker for cancer. Histone deacetylase inhibitors (HDACis) have considerable potential for cancer therapy, however, the effects of HDACis on ion channel expression have not yet been investigated in detail. The results of this study showed a significant decrease in K_Ca3.1 transcription by HDAC inhibition in the human breast cancer cell line YMB‐1, which functionally expresses K_Ca3.1. A treatment with the clinically available, class I, II, and IV HDAC inhibitor, vorinostat significantly downregulated K_Ca3.1 transcription in a concentration‐dependent manner, and the plasmalemmal expression of the K_Ca3.1 protein and its functional activity were correspondingly decreased. Pharmacological and siRNA‐based HDAC inhibition both revealed the involvement of HDAC2 and HDAC3 in K_Ca3.1 transcription through the same mechanism. The downregulation of K_Ca3.1 in YMB‐1 was not due to the upregulation of the repressor element‐1 silencing transcription factor, REST and the insulin‐like growth factor‐binding protein 5, IGFBP5. The significant decrease in K_Ca3.1 transcription by HDAC inhibition was also observed in the K_Ca3.1‐expressing human prostate cancer cell line, PC‐3. These results suggest that vorinostat and the selective HDACis for HDAC2 and/or HDAC3 are effective drug candidates for K_Ca3.1‐overexpressing cancers.