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Suberoylanilide Hydroxamic Acid Enhances Gap Junctional Intercellular Communication via Acetylation of Histone Containing Connexin 43 Gene Locus

¹ Department of Radiobiology and Molecular Epidemiology, Radiation Effects Research Foundation; ² Department of Molecular and Internal Medicine, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan; and ³ National Food Safety Toxicology Center, Department of Pediatrics/Human Development, Michigan State University, East Lansing, Michigan

Requests for reprints: Takahiko Ogawa or Tomonori Hayashi, Department of Radiobiology and Molecular Epidemiology, Radiation Effects Research Foundation, 5-2, Hijiyama Park, Minami Ward, 732-0815 Hiroshima, Japan. Phone: 81-82-261-3131; Fax: 81-82-261-3170; E-mail: tk-ogawa{at}hph.pref.hiroshima.jp or tomo{at}rerf.or.jp.

A histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA), induces apoptosis in neoplastic cells, but its effect on gap junctional intercellular communication in relation to apoptosis was unclear. Therefore, we carried out a comparative study of the effects of two HDAC inhibitors, SAHA and trichostatin-A, on gap junctional intercellular communication in nonmalignant human peritoneal mesothelial cells (HPMC) and tumorigenic ras oncogene–transformed rat liver epithelial cells (WB-ras) that showed a significantly lower level of gap junctional intercellular communication than did HPMC. Gap junctional intercellular communication was assessed by recovery rate of fluorescence recovery after photobleaching. Treatment of HPMC with SAHA at nanomolar concentrations caused a dose-dependent increase of recovery rate without inducing apoptosis. This effect was accompanied by enhanced connexin 43 (Cx43) mRNA and protein expression and increased presence of Cx43 protein on cell membrane. Trichostatin-A induced apoptosis in HPMC but was less potent than SAHA in enhancing the recovery rate. In contrast, treatment of WB-ras cells with SAHA or trichostatin-A induced apoptosis at low concentrations, in spite of smaller increases in recovery rate, Cx43 mRNA, and protein than in HPMC. Chromatin immunoprecipitation analysis revealed that SAHA enhanced acetylated histones H3 and H4 in the chromatin fragments associated with Cx43 gene in HPMC. These results indicate that SAHA at low concentrations selectively up-regulates Cx43 expression in normal human cells without induction of apoptosis, as a result of histone acetylation in selective chromatin fragments, in contrast to the apoptotic effect observed in tumorigenic WB-ras cells. These results support a cancer therapeutic and preventive role for specific HDAC inhibitors.

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