title: The polycomb group protein Bmi-1 represses the tumor suppressor PTEN and induces epithelial-mesenchymal transition in human nasopharyngeal epithelial cells.
abstract: The polycomb group protein B lymphoma Mo-MLV insertion region 1 homolog (Bmi-1) is dysregulated in various cancers, and its upregulation strongly correlates with an invasive phenotype and poor prognosis in patients with nasopharyngeal carcinomas. However, the underlying mechanism of Bmi-1-mediated invasiveness remains unknown. In the current study, we found that upregulation of Bmi-1 induced epithelial-mesenchymal transition (EMT) and enhanced the motility and invasiveness of human nasopharyngeal epithelial cells, whereas silencing endogenous Bmi-1 expression reversed EMT and reduced motility. Furthermore, upregulation of Bmi-1 led to the stabilization of Snail, a transcriptional repressor associated with EMT, via modulation of PI3K/Akt/GSK-3beta signaling. Chromatin immunoprecipitation assays revealed that Bmi-1 transcriptionally downregulated expression of the tumor suppressor PTEN in tumor cells through direct association with the PTEN locus. This in vitro analysis was consistent with the statistical inverse correlation detected between Bmi-1 and PTEN expression in a cohort of human nasopharyngeal carcinoma biopsies. Moreover, ablation of PTEN expression partially rescued the migratory/invasive phenotype of Bmi-1-silenced cells, indicating that PTEN might be a major mediator of Bmi-1-induced EMT. Our results provide functional and mechanistic links between the oncoprotein Bmi-1 and the tumor suppressor PTEN in the development and progression of cancer.
authors.affiliation: State Key Laboratory of Oncology in South China, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China.
authors.forename: Li-Bing
authors.initials: LB
authors.lastname: Song
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Wen-Ting
authors.initials: WT
authors.lastname: Liao
authors.forename: Yan
authors.initials: Y
authors.lastname: Feng
authors.forename: Chun-Ping
authors.initials: CP
authors.lastname: Yu
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Hu
authors.forename: Qing-Li
authors.initials: QL
authors.lastname: Kong
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Xu
authors.forename: Xing
authors.initials: X
authors.lastname: Zhang
authors.forename: Wan-Li
authors.initials: WL
authors.lastname: Liu
authors.forename: Man-Zhi
authors.initials: MZ
authors.lastname: Li
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.forename: Tie-Bang
authors.initials: TB
authors.lastname: Kang
authors.forename: Li-Wu
authors.initials: LW
authors.lastname: Fu
authors.forename: Wen-Lin
authors.initials: WL
authors.lastname: Huang
authors.forename: Yun-Fei
authors.initials: YF
authors.lastname: Xia
authors.forename: Sai Wah
authors.initials: SW
authors.lastname: Tsao
authors.forename: Mengfeng
authors.initials: M
authors.lastname: Li
authors.forename: Vimla
authors.initials: V
authors.lastname: Band
authors.forename: Hamid
authors.initials: H
authors.lastname: Band
authors.forename: Qing-Hua
authors.initials: QH
authors.lastname: Shi
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Zeng
authors.forename: Mu-Sheng
authors.initials: MS
authors.lastname: Zeng
mesh_terms: D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D020868:Gene Silencing; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009303:Nasopharyngeal Neoplasms / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009305:Nasopharynx / Q000166:cytology* / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D063150:Polycomb Repressive Complex 1; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012097:Repressor Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: C069077:BMI1 protein, human; D015820:Cadherins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D063150:Polycomb Repressive Complex 1; D019869:Phosphatidylinositol 3-Kinases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human