期刊
ONCOTARGET
卷 7, 期 27, 页码 41540-41558出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.9236
关键词
EZH2; cancer stem-like cell; colorectal cancer; cell cycle; p21(cip1)
资金
- National Natural Science Foundation of China [81101629]
Because colorectal cancer (CRC) stem- like cells (CCS- like cells) contribute to poor patient prognosis, these cells are a potential target for CRC therapy. However, the mechanism underlying the maintenance of CCS- like cell properties remains unclear. Here, we found that patients with advanced stage CRC expressed high levels of polycomb group protein enhancer of zeste homologue 2 (EZH2). High expression of EZH2 in tumor tissues correlated with poor patient prognosis. Conversely, silencing EZH2 reduced CRC cell proliferation. Surprisingly, EZH2 was more highly expressed in the CCS- like cell subpopulation than in the non-CCS-like cell subpopulation. EZH2 knockdown significantly reduced the CD133(+)/CD44(+) subpopulation, suppressed mammosphere formation, and decreased the expression of self-renewal-related genes and strongly impaired tumor-initiating capacity in a re-implantation mouse model. Gene expression data from 433 human CRC specimens from TCGA database and in vitro results revealed that EZH2 helped maintain CCS- like cell properties by activating the Wnt/beta-catenin pathway. We further revealed that p21(cip1)-mediated arrest of the cell cycle at G1/S phase is required for EZH2 activation of the Wnt/beta-catenin pathway. Moreover, the specific EZH2 inhibitor EPZ-6438, a clinical trial drug, prevented CRC progression. Collectively, these findings revealed EZH2 maintaining CCS- like cell characteristics by arresting the cell cycle at the G1/S phase. These results indicate a new approach to CRC therapy.
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