title: c-Rel regulates Ezh2 expression in activated lymphocytes and malignant lymphoid cells.
abstract: The polycomb group protein Ezh2 is a histone methyltransferase that modifies chromatin structure to alter gene expression during embryonic development, lymphocyte activation, and tumorigenesis. The mechanism by which Ezh2 expression is regulated is not well defined. In the current study, we report that c-Rel is a critical activator of Ezh2 transcription in lymphoid cells. In activated primary murine B and T cells, plus human leukemia and multiple myeloma cell lines, recruitment of c-Rel to the first intron of the Ezh2 locus promoted Ezh2 mRNA expression. This up-regulation was abolished in activated c-Rel-deficient lymphocytes and by c-Rel knockdown in Jurkat T cells. Treatment of malignant cells with the c-Rel inhibitor pentoxifylline not only reduced c-Rel nuclear translocation and Ezh2 expression, but also enhanced their sensitivity to the Ezh2-specific drug, GSK126 through increased growth inhibition and cell death. In summary, our demonstration that c-Rel regulates Ezh2 expression in lymphocytes and malignant lymphoid cells reveals a novel transcriptional network in transformed lymphoid cells expressing high levels of Ezh2 that provides a molecular justification for combinatorial drug therapy.
authors.affiliation: School of Biological Sciences, College of Science, Nanyang Technological University, Singapore 637551, Republic of Singapore and.
authors.forename: Wen Hao
authors.initials: WH
authors.lastname: Neo
authors.affiliation: School of Biological Sciences, College of Science, Nanyang Technological University, Singapore 637551, Republic of Singapore and.
authors.forename: Jun Feng
authors.initials: JF
authors.lastname: Lim
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria 3004, Australia.
authors.forename: Raelene
authors.initials: R
authors.lastname: Grumont
authors.affiliation: Australian Centre for Blood Diseases, Monash University, Melbourne, Victoria 3004, Australia.
authors.forename: Steve
authors.initials: S
authors.lastname: Gerondakis
authors.affiliation: School of Biological Sciences, College of Science, Nanyang Technological University, Singapore 637551, Republic of Singapore and. Electronic address: ihsu@ntu.edu.sg.
authors.forename: I-Hsin
authors.initials: IH
authors.lastname: Su
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D002470:Cell Survival; D000071221:Enhancer of Zeste Homolog 2 Protein; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D007211:Indoles / Q000737:chemistry; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D008214:Lymphocytes / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000378:metabolism; D010431:Pentoxifylline / Q000737:chemistry; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism*; D020569:Proto-Oncogene Proteins c-rel / Q000378:metabolism*; D011728:Pyridones / Q000737:chemistry; D014158:Transcription, Genetic; D015854:Up-Regulation
chemical_list: C577920:GSK-2816126; D007211:Indoles; D020569:Proto-Oncogene Proteins c-rel; D011728:Pyridones; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; C498410:Ezh2 protein, mouse; D063151:Polycomb Repressive Complex 2; D010431:Pentoxifylline
keywords: Gene Regulation; Leukemia; Lymphocyte; Lymphoma; Polycomb; Transcription Factor