TY - JOUR
T1 - Inhibitors of enhancer of zeste homolog 2 (EZH2) activate tumor-suppressor microRNAs in human cancer cells
AU - Hibino, S.
AU - Saito, Y.
AU - Muramatsu, T.
AU - Otani, A.
AU - Kasai, Y.
AU - Kimura, M.
AU - Saito, Hidetsugu
N1 - Funding Information:
This work was supported by Grant-in-Aid for Young Scientists A (23680090) from the Japan Society for Promotion of Science, Takeda Science Foundation, Science Research Promotion Fund from the Promotion and Mutual Aid Corporation for Private Schools in Japan and Keio Gijuku Academic Development Fund.
PY - 2014/1/1
Y1 - 2014/1/1
N2 - Enhancer of zeste homolog 2 (EZH2) enhances tumorigenesis and is commonly overexpressed in several types of cancer. To investigate the anticancer effects of EZH2 inhibitors, microRNA (miRNA) expression profiles were examined in gastric and liver cancer cells treated with suberoylanilide hydroxamic acid (SAHA) and 3-deazaneplanocin A (DZNep). We confirmed that SAHA and DZNep suppressed EZH2 expression in AGS and HepG2 cells and inhibited their proliferation. The results of microarray analyses demonstrated that miR-1246 was commonly upregulated in cancer cells by treatment with SAHA and DZNep. MiR-302a and miR-4448 were markedly upregulated by treatment with SAHA and DZNep, respectively. DYRK1A, CDK2, BMI-1 and Girdin, which are targets of miR-1246, miR-302a and miR-4448, were suppressed by treatment with SAHA and DZNep, leading to apoptosis, cell cycle arrest and reduced migration of AGS and HepG2 cells. ChIP assay revealed that SAHA and DZNep inhibited the binding of EZH2 to the promoter regions of miR-1246, miR-302a and miR-4448. These findings suggest that EZH2 inhibitors such as SAHA and DZNep exert multiple anticancer effects through activation of tumor-suppressor miRNAs.
AB - Enhancer of zeste homolog 2 (EZH2) enhances tumorigenesis and is commonly overexpressed in several types of cancer. To investigate the anticancer effects of EZH2 inhibitors, microRNA (miRNA) expression profiles were examined in gastric and liver cancer cells treated with suberoylanilide hydroxamic acid (SAHA) and 3-deazaneplanocin A (DZNep). We confirmed that SAHA and DZNep suppressed EZH2 expression in AGS and HepG2 cells and inhibited their proliferation. The results of microarray analyses demonstrated that miR-1246 was commonly upregulated in cancer cells by treatment with SAHA and DZNep. MiR-302a and miR-4448 were markedly upregulated by treatment with SAHA and DZNep, respectively. DYRK1A, CDK2, BMI-1 and Girdin, which are targets of miR-1246, miR-302a and miR-4448, were suppressed by treatment with SAHA and DZNep, leading to apoptosis, cell cycle arrest and reduced migration of AGS and HepG2 cells. ChIP assay revealed that SAHA and DZNep inhibited the binding of EZH2 to the promoter regions of miR-1246, miR-302a and miR-4448. These findings suggest that EZH2 inhibitors such as SAHA and DZNep exert multiple anticancer effects through activation of tumor-suppressor miRNAs.
KW - DZNep
KW - EZH2
KW - SAHA
KW - cancer
KW - microRNA
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UR - http://www.scopus.com/inward/citedby.url?scp=84927709697&partnerID=8YFLogxK
U2 - 10.1038/oncsis.2014.17
DO - 10.1038/oncsis.2014.17
M3 - Article
AN - SCOPUS:84927709697
SN - 2157-9024
VL - 3
JO - Oncogenesis
JF - Oncogenesis
IS - 5
M1 - e104
ER -
