Polycomb group protein EZH2, frequently overexpressed in malignant
tumors, is the catalytic subunit of
polycomb repressive complex 2 (PRC2). PRC2 interacts with HDACs in transcriptional silencing and relates to
tumor suppressor loss. We examined the expression of HDAC
isoforms (HDAC 1 and 2) and EZH2, and evaluated the possible use of
HDAC inhibitor suberoylanilide hydroxamic acid (SAHA) and EZH2 repressor for gallbladder
carcinoma. We used 48 surgically resected gallbladders and cultures of human gallbladder epithelial cells (HGECs), gallbladder
carcinoma (TGBC2TKB), and
cholangiocarcinoma (HuCCT-1 and TFK-1) cell lines for examination. Immunohistochemically, EZH2 was overexpressed in gallbladder
carcinoma, especially poorly differentiated
carcinoma, but not in normal epithelium. In contrast, HDAC1/2 were expressed in both
carcinoma and normal epithelium in vivo. This pattern was verified in cultured cells; EZH2 was highly expressed only in TGBC2TKB, whereas HDAC1/2 were expressed in HGECs and TGBC2TKB. Interestingly, SAHA treatment caused significant cell number decline in three
carcinoma cells, and this effect was synergized with EZH2
siRNA treatment; however, HGECs were resistant to SAHA. In TGBC2TKB cells, the expression of EZH2 and HDAC1/2 were decreased by SAHA treatment, and
p16(INK4a),
E-cadherin, and p21were simultaneously activated; however, no such findings were obtained in HGECs, suggesting that the effect of SAHA depends on the EZH2-mediated
tumor suppressor loss. In conclusion, this study suggests a possible mechanism by which
carcinoma cells but not normal cells are sensitive to SAHA and indicates the efficacy of this new
anticancer agent in combination with EZH2 repression in gallbladder
carcinoma.