title: EZH2 promotes colorectal cancer stem-like cell expansion by activating p21cip1-Wnt/β-catenin signaling.
abstract: 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.
authors.affiliation: Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Jian-Fang
authors.initials: JF
authors.lastname: Chen
authors.affiliation: Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Luo
authors.affiliation: State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Sichuan, China.
authors.forename: Li-Sha
authors.initials: LS
authors.lastname: Xiang
authors.affiliation: Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Hong-Tao
authors.initials: HT
authors.lastname: Li
authors.affiliation: Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Zha
authors.affiliation: Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Ni
authors.initials: N
authors.lastname: Li
authors.affiliation: Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Jian-Ming
authors.initials: JM
authors.lastname: He
authors.affiliation: Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Gan-Feng
authors.initials: GF
authors.lastname: Xie
authors.affiliation: Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Xiong
authors.initials: X
authors.lastname: Xie
authors.affiliation: Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Hou-Jie
authors.initials: HJ
authors.lastname: Liang
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology*; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000502:physiology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D060449:Wnt Signaling Pathway / Q000235:genetics; D055815:Young Adult; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C493956:CDKN1A protein, human; C495270:CTNNB1 protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D051176:beta Catenin; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein
keywords: EZH2; cancer stem-like cell; cell cycle; colorectal cancer; p21cip1