Journal
ONCOTARGET
Volume 5, Issue 21, Pages 10342-10355Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.1867
Keywords
EZH2; NSC745885; proteasome degradation; G2/M cell-cycle arrest
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Funding
- National Science Council [NSC101-2314-B-016-004-MY3, NSC99-2628-B-016-012-MY3]
- Tri-Service General Hospital Research Foundation, Taiwan, ROC [TSGH-C99-012-13-S01, TSGH-C103-005-007-009-S02]
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The polycomb group gene, EZH2, is highly expressed in advanced bladder cancer. Here we demonstrated that down-regulation of EZH2 in tumor tissues after neoadjuvant chemotherapy correlated with good therapeutic response in advanced bladder cancer. We next developed a small molecule, NSC745885, derived from natural anthraquinone emodin, which down-regulated EZH2 via proteasome-mediated degradation. NSC745885 showed potent selective toxicity against multiple cancer cell lines but not normal cells. NSC745885 treatment overcame multiple-drug resistance and inhibited growth of resistant cancer cells. Over-expression of EZH2 in cancer cells attenuated effects of NSC745885, suggesting that down-regulation of EZH2 was responsible for growth inhibition of NSC745885. NSC745885 also suppressed tumor growth and down-regulated EZH2 in vivo. These results indicate that NSC7455889 suppresses bladder cancer by targeting EZH2.
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