Microtubule-associated histone deacetylase 6 supports the calcium store sensor STIM1 in mediating malignant cell behaviors

Ying Ting Chen, Yih Fung Chen, Wen Tai Chiu, Kuan Yu Liu, Yu Lin Liu, Jang Yang Chang, Hsien Chang Chang, Meng Ru Shen

Research output: Contribution to journalArticlepeer-review

34 Citations (Scopus)

Abstract

Stromal-interaction molecule 1 (STIM1) is an endoplasmic reticulum Ca 2+ storage sensor that promotes cell growth, migration, and angiogenesis in breast and cervical cancers. Here, we report that the microtubule-associated histone deacetylase 6 (HDAC6) differentially regulates activation of STIM1-mediated store-operated Ca2+ entry (SOCE) between cervical cancer cells and normal cervical epithelial cells. Confocal microscopy of living cells indicated that microtubule integrity was necessary for STIM1 trafficking to the plasma membrane and interaction with Orai1, an essential pore subunit of SOCE. Cancer cells overexpressed both STIM1 and Orai1 compared with normal cervical epithelial cells. HDAC6 upregulation in cancer cells was accompanied by hypoacetylated a-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. Genetic or pharmacologic inhibition of HDAC6 blocked STIM1 membrane trafficking and downstream Ca2+ influx, as evidenced by total internal reflection fluorescent images and intracellular Ca2+ determination. 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 a-tubulin. Together, our results identify HDAC6 as a candidate target to disrupt STIM1-mediated SOCE as a general strategy to block malignant cell behavior.

Original languageEnglish
Pages (from-to)4500-4509
Number of pages10
JournalCancer Research
Volume73
Issue number14
DOIs
Publication statusPublished - 2013 Jul 15

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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