Volume 27 Issue 9 - November 7, 2014 PDF
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Microtubule-associated histone deacetylase 6 supports the calcium store sensor STIM1 in mediating malignant cell behaviors
Ying-Ting Chen1, Yih-Fung Chen2, Wen-Tai Chiu1,3, Kuan-Yu Liu2, Yu-Lin Liu2, Jang-Yang Chang8, Hsien-Chang Chang1,4, Meng-Ru Shen2,5,6,7,*
1 Departments of Biomedical Engineering, National Cheng Kung University, Tainan 701, Taiwan
2 Departments of Pharmacology, National Cheng Kung University, Tainan 701, Taiwan
3 Institute of Basic Medical Sciences, National Cheng Kung University, Tainan 701, Taiwan
4 Medical Device Innovation Center, National Cheng Kung University, Tainan 701, Taiwan
5 Departments of Obstetrics and Gynecology, National Cheng Kung University Hospital, Tainan 704, Taiwan
6 Advanced Optoelectronic Technology Center, National Cheng Kung University, Tainan 701, Taiwan
7 Infectious Diseases and Signaling Research Center, National Cheng Kung University, Tainan 701, Taiwan
8 National Institute of Cancer Research, National Health Research Institutes, Tainan 704, Taiwan
 
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Modulation of intracellular Ca2+ levels provides versatile and dynamic signaling that mediates various cellular processes, such as proliferation, migration, and gene expression. Store-operated Ca2+ entry (SOCE) is the major form of extracellular Ca2+ influx in non-excitable cells, and the major molecular components in regulation of SOCE are the ER Ca2+ sensor stromal interaction molecule1 (STIM1) and two plasma membrane Ca2+ channels transient receptor potential channel 1 (TRPC1) and Orai1. The clinical relevance of STIM1 has been highlighted in breast and cervical cancer. Here, we reported that the microtubule-associated histone deacetylase 6 (HDAC6) differentially regulates activation of SOCE. We found that microtubule integrity was necessary for STIM1 trafficking to the plasma membrane and interaction with Orai1. Cancer cells overexpressed both STIM1 and Orai1 compared with normal cervical epithelial cells. HDAC6 upregulation in cancer cells was accompanied by hypoacetylated α-tubulin. Tubastatin-A, a specific HDAC6 inhibitor, inhibited STIM1 translocation to plasma membrane and blocked SOCE activation in cancer cells but not normal epithelial cells. Moreover, this phenomenon was also observed by using the siRNA knockdown of HDAC6. In contrast, HDAC6 inhibition did not affect interactions between STIM1 and the microtubule plus end-binding protein EB1. Analysis of surgical specimens confirmed that most cervical cancer tissues overexpressed STIM1 and Orai1, accompanied by hypoacetylated α-tubulin. Taken together, our results identify HDAC6 as a candidate target to disrupt STIM1-mediated SOCE as a general strategy to block malignant cell behavior.

Figure 1. HDAC6 inhibitor, tubastatin-A, blocks STIM1 membrane tracking.
Cervical cancer HeLa cells overexpressing EGFP-STIM1 and RFP-plasma membrane proteins were preincubated with 0.1% DMSO or 5 μM tubastatin-A for 10 hours prior to TG (2 μM, 10 minutes) stimulation. Representative images of EGFP-STIM1 and RFP-plasma membrane proteins were taken under confocal microscope.
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