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 journalArticle

30 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

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Histone Deacetylases
Microtubules
Calcium
Uterine Cervical Neoplasms
Epithelial Cells
Tubulin
Cell Membrane
Stromal Interaction Molecule 1
Neoplasms
Histone Deacetylase Inhibitors
Confocal Microscopy
Endoplasmic Reticulum
Cell Movement
Carrier Proteins
Up-Regulation
Breast Neoplasms
Membranes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

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title = "Microtubule-associated histone deacetylase 6 supports the calcium store sensor STIM1 in mediating malignant cell behaviors",
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.",
author = "Chen, {Ying Ting} and Chen, {Yih Fung} and Wen-Tai Chiu and Liu, {Kuan Yu} and Liu, {Yu Lin} and Jang-Yang Chang and Hsien-Chang Chang and Meng-Ru Shen",
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Microtubule-associated histone deacetylase 6 supports the calcium store sensor STIM1 in mediating malignant cell behaviors. / Chen, Ying Ting; Chen, Yih Fung; Chiu, Wen-Tai; Liu, Kuan Yu; Liu, Yu Lin; Chang, Jang-Yang; Chang, Hsien-Chang; Shen, Meng-Ru.

In: Cancer Research, Vol. 73, No. 14, 15.07.2013, p. 4500-4509.

Research output: Contribution to journalArticle

TY - JOUR

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AU - Chen, Ying Ting

AU - Chen, Yih Fung

AU - Chiu, Wen-Tai

AU - Liu, Kuan Yu

AU - Liu, Yu Lin

AU - Chang, Jang-Yang

AU - Chang, Hsien-Chang

AU - Shen, Meng-Ru

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