The BMI1 polycomb protein represses cyclin G2-induced autophagy to support proliferation in chronic myeloid leukemia cells
| Autor: | P Lagadec, Estelle Duprez, Zouhour Neffati, Els Verhoeyen, Véronique Maguer-Satta, Véronique Imbert, J F Peyron, Chun Peng, L Mourgues, Didier Mary, Laurence Legros, F-E Nicolini, Pascal Colosetti, Marielle Nebout, Nathalie Rochet |
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| Rok vydání: | 2015 |
| Předmět: |
Chromatin Immunoprecipitation
Cancer Research Blotting Western Cyclin G2 Apoptosis macromolecular substances Biology Downregulation and upregulation Leukemia Myelogenous Chronic BCR-ABL Positive hemic and lymphatic diseases Autophagy Tumor Cells Cultured medicine Humans RNA Small Interfering Clonogenic assay Cell Proliferation Cyclin Polycomb Repressive Complex 1 Gene Expression Regulation Leukemic Myeloid leukemia Hematology medicine.disease Leukemia Oncology BMI1 Cancer research Ectopic expression Signal Transduction |
| Zdroj: | Leukemia. 29:1993-2002 |
| ISSN: | 1476-5551 0887-6924 |
| DOI: | 10.1038/leu.2015.112 |
| Popis: | The BMI1 polycomb protein regulates self-renewal, proliferation and survival of cancer-initiating cells essentially through epigenetic repression of the CDKN2A tumor suppressor locus. We demonstrate here for the first time that BMI1 also prevents autophagy in chronic myeloid leukemia (CML) cell lines, to support their proliferation and clonogenic activity. Using chromatin immunoprecipitation, we identified CCNG2/cyclin G2 (CCNG2) as a direct BMI1 target. BMI1 downregulation in CD34+ CML cells by PTC-209 pharmacological treatment or shBMI1 transduction triggered CCNG2 expression and decreased clonogenic activity. Also, ectopic expression of CCNG2 in CD34+ CML cells strongly decreased their clonogenicity. CCNG2 was shown to act by disrupting the phosphatase 2A complex, which activates a PKCζ-AMPK-JNK-ERK pathway that engages autophagy. We observed that BMI1 and CCNG2 levels evolved inversely during the progression of CML towards an acute deadly phase, and therefore hypothesized that BMI1 could support acute transformation of CML through the silencing of a CCNG2-mediated tumor-suppressive autophagy response. |
| Databáze: | OpenAIRE |
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