The polycomb group protein Bmi-1 represses the tumor suppressor PTEN and induces epithelial-mesenchymal transition in human nasopharyngeal epithelial cells

Li Bing Song, Jun Li, Wen Ting Liao, Yan Feng, Chun Ping Yu, Li Juan Hu, Qing Li Kong, Li Hua Xu, Xing Zhang, Wan Li Liu, Man Zhi Li, Ling Zhang, Tie Bang Kang, Li Wu Fu, Wen Lin Huang, Yun Fei Xia, Sai Wah Tsao, Mengfeng Li, Vimla Band, Hamid BandQing Hua Shi, Yi Xin Zeng, Mu Sheng Zeng

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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 epithelialmesenchymal 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-3β 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.

Original languageEnglish (US)
Pages (from-to)3626-3636
Number of pages11
JournalJournal of Clinical Investigation
Volume119
Issue number12
DOIs
StatePublished - Dec 1 2009

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Polycomb-Group Proteins
Epithelial-Mesenchymal Transition
Epithelial Cells
Up-Regulation
Neoplasms
Glycogen Synthase Kinase 3
Phenotype
Chromatin Immunoprecipitation
Oncogene Proteins
Phosphatidylinositol 3-Kinases
Lymphoma
Down-Regulation
Biopsy

ASJC Scopus subject areas

  • Medicine(all)

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The polycomb group protein Bmi-1 represses the tumor suppressor PTEN and induces epithelial-mesenchymal transition in human nasopharyngeal epithelial cells. / Song, Li Bing; Li, Jun; Liao, Wen Ting; Feng, Yan; Yu, Chun Ping; Hu, Li Juan; Kong, Qing Li; Xu, Li Hua; Zhang, Xing; Liu, Wan Li; Li, Man Zhi; Zhang, Ling; Kang, Tie Bang; Fu, Li Wu; Huang, Wen Lin; Xia, Yun Fei; Tsao, Sai Wah; Li, Mengfeng; Band, Vimla; Band, Hamid; Shi, Qing Hua; Zeng, Yi Xin; Zeng, Mu Sheng.

In: Journal of Clinical Investigation, Vol. 119, No. 12, 01.12.2009, p. 3626-3636.

Research output: Contribution to journalArticle

Song, LB, Li, J, Liao, WT, Feng, Y, Yu, CP, Hu, LJ, Kong, QL, Xu, LH, Zhang, X, Liu, WL, Li, MZ, Zhang, L, Kang, TB, Fu, LW, Huang, WL, Xia, YF, Tsao, SW, Li, M, Band, V, Band, H, Shi, QH, Zeng, YX & Zeng, MS 2009, 'The polycomb group protein Bmi-1 represses the tumor suppressor PTEN and induces epithelial-mesenchymal transition in human nasopharyngeal epithelial cells', Journal of Clinical Investigation, vol. 119, no. 12, pp. 3626-3636. https://doi.org/10.1172/JCI39374
Song, Li Bing ; Li, Jun ; Liao, Wen Ting ; Feng, Yan ; Yu, Chun Ping ; Hu, Li Juan ; Kong, Qing Li ; Xu, Li Hua ; Zhang, Xing ; Liu, Wan Li ; Li, Man Zhi ; Zhang, Ling ; Kang, Tie Bang ; Fu, Li Wu ; Huang, Wen Lin ; Xia, Yun Fei ; Tsao, Sai Wah ; Li, Mengfeng ; Band, Vimla ; Band, Hamid ; Shi, Qing Hua ; Zeng, Yi Xin ; Zeng, Mu Sheng. / The polycomb group protein Bmi-1 represses the tumor suppressor PTEN and induces epithelial-mesenchymal transition in human nasopharyngeal epithelial cells. In: Journal of Clinical Investigation. 2009 ; Vol. 119, No. 12. pp. 3626-3636.
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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 epithelialmesenchymal 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-3β 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.",
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T1 - The polycomb group protein Bmi-1 represses the tumor suppressor PTEN and induces epithelial-mesenchymal transition in human nasopharyngeal epithelial cells

AU - Song, Li Bing

AU - Li, Jun

AU - Liao, Wen Ting

AU - Feng, Yan

AU - Yu, Chun Ping

AU - Hu, Li Juan

AU - Kong, Qing Li

AU - Xu, Li Hua

AU - Zhang, Xing

AU - Liu, Wan Li

AU - Li, Man Zhi

AU - Zhang, Ling

AU - Kang, Tie Bang

AU - Fu, Li Wu

AU - Huang, Wen Lin

AU - Xia, Yun Fei

AU - Tsao, Sai Wah

AU - Li, Mengfeng

AU - Band, Vimla

AU - Band, Hamid

AU - Shi, Qing Hua

AU - Zeng, Yi Xin

AU - Zeng, Mu Sheng

PY - 2009/12/1

Y1 - 2009/12/1

N2 - 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 epithelialmesenchymal 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-3β 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.

AB - 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 epithelialmesenchymal 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-3β 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.

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