EZH2 promotes colorectal cancer stem-like cell expansion by activating p21cip1-Wnt/β-catenin signaling
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Jian-Fang Chen1,*, Xi Luo1,*, Li-Sha Xiang2, Hong-Tao Li1, Lin Zha1, Ni Li1, Jian-Ming He1, Gan-Feng Xie1, Xiong Xie1, Hou-Jie Liang1
1Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China
2State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Sichuan, China
*These authors have contributed equally to this work
Hou-Jie Liang, email: firstname.lastname@example.org
Keywords: EZH2, cancer stem-like cell, colorectal cancer, cell cycle, p21cip1
Received: December 18, 2015 Accepted: April 24, 2016 Published: May 9, 2016
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/β-catenin pathway. We further revealed that p21cip1–mediated arrest of the cell cycle at G1/S phase is required for EZH2 activation of the Wnt/β-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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