TTYH1 and TTYH2 Serve as LRRC8A-Independent Volume-Regulated Anion Channels in Cancer Cells
TTYH1 and TTYH2 Serve as LRRC8A-Independent Volume-Regulated Anion Channels in Cancer Cells
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DOI：
10.3390/cells8060562
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发表时间：
2019-06-01
期刊：
影响因子：
6
通讯作者：
Hwang, Eun Mi
中科院分区：
文献类型：
--
作者：
Bae, Yeonju;Kim, Ajung;Hwang, Eun Mi
体积调节阴离子通道（VRAC）参与细胞功能，如调节细胞体积、增殖、迁移和细胞死亡。虽然富含亮氨酸的重复序列8A（LRRC 8A）已被表征为VRAC的分子组成部分，在这里，我们表明，果蝇tweety同源物1和2（TTYH 1和TTYH 2）是癌细胞中VRAC电流的关键。LRRC 8A非依赖性VRAC电流存在于胃癌细胞系SNU-601中，但在其顺铂耐药衍生物SNU-601-R10（R10）中几乎完全不存在。用组蛋白去乙酰化酶抑制剂阿司他丁A（TSA）处理，R10中的VRAC电流部分恢复。基于这些细胞的微阵列表达谱，我们选择了两个氯离子通道TTYH 1和TTYH 2作为VRAC候选者。TTYH 1和TTYH 2缺陷SNU-601细胞中完全不存在VRAC电流，并且通过TTYH 1或TTYH 2的表达而明显恢复。此外，我们检测了TTYH 1或TTYH 2在几种癌细胞系中的表达，发现TTYH 1或TTYH 2的基因沉默消除了这些细胞的VRAC电流。总之，我们的数据清楚地表明TTYH 1和TTYH 2可以作为LRRC 8A独立的VRAC，这表明了癌细胞中VRAC的新治疗方法。
Volume-regulated anion channels (VRACs) are involved in cellular functions such as regulation of cell volume, proliferation, migration, and cell death. Although leucine-rich repeat-containing 8A (LRRC8A) has been characterized as a molecular component of VRACs, here we show that Drosophila melanogaster tweety homologue 1 and 2 (TTYH1 and TTYH2) are critical for VRAC currents in cancer cells. LRRC8A-independent VRAC currents were present in the gastric cancer cell line SNU-601, but almost completely absent in its cisplatin-resistant derivative SNU-601-R10 (R10). The VRAC current in R10 was partially restored by treatment with trichostatin A (TSA), a histone deacetylase inhibitor. Based on microarray expression profiling of these cells, we selected two chloride channels, TTYH1 and TTYH2, as VRAC candidates. VRAC currents were completely absent from TTYH1- and TTYH2-deficient SNU-601 cells, and were clearly restored by expression of TTYH1 or TTYH2. In addition, we examined the expression of TTYH1 or TTYH2 in several cancer cell lines and found that VRAC currents of these cells were abolished by gene silencing of TTYH1 or TTYH2. Taken together, our data clearly show that TTYH1 and TTYH2 can act as LRRC8A-independent VRACs, suggesting novel therapeutic approaches for VRACs in cancer cells.