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Association of Estrogen Receptor and Histone Deacetylase 6 Causes Rapid Deacetylation of Tubulin in Breast Cancer Cells

Departments of ¹ Geriatric Medicine and ² Anti-Aging Medicine, Graduate School of Medicine, The University of Tokyo and ³ Growth Factor Division, National Cancer Center Research Institute, Tokyo, Japan; ⁴ Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical School, Saitama, Japan; and ⁵ Department of Medical Technology, Course of Health Sciences, School of Medicine, Tohoku University, Miyagi, Japan

Requests for reprints: Satoshi Inoue, Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. Phone: 81-3-5800-8652; Fax: 81-3-5800-6530; E-mail: INOUE-GER{at}h.u-tokyo.ac.jp.

Key Words: ER • breast cancer • HDAC6 • nongenomic action • tubulin

Estrogen receptor (ER) is a nuclear receptor that functions as a ligand-activated transcription factor. Besides its genomic action in nuclei, ER could exert nongenomic actions at the plasma membrane. To investigate the mechanism underlying the nongenomic action of ER in breast cancer cells, we generated a construct of membrane-targeted ER (memER), an expression vector of ER without the nuclear localizing signal and including instead the membrane-targeting sequence of Src kinase. MemER was stably expressed in human breast cancer MCF-7 cells. Cell migration test and tumorigenic assay in nude mice revealed that the in vitro motility and the in vivo proliferation activity of MCF-7 cells expressing memER were significantly enhanced compared with those of vector-transfected cells. Interestingly, the acetylation level of tubulin in memER-overexpressing cells was lower than that in control cells. We found that histone deacetylase (HDAC) 6 translocated to the plasma membrane shortly after estrogen stimulation, and rapid tubulin deacetylation subsequently occurred. We also showed that memER associated with HDAC6 in a ligand-dependent manner. Although tamoxifen is known for its antagonistic role in the ER genomic action in MCF-7 cells, the agent showed an agonistic function in the memER-HDAC6 association and tubulin deacetylation. These findings suggest that ER ligand dependently forms a complex with HDAC6 and tubulin at the plasma membrane. Estrogen-dependent tubulin deacetylation could provide new evidence for the nongenomic action of estrogen, which potentially contributes to the aggressiveness of ER-positive breast cancer cells. [Cancer Res 2009;69(7):2935–40]

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