title: LEO1 is regulated by PRL-3 and mediates its oncogenic properties in acute myelogenous leukemia.
abstract: PRL-3, an oncogenic dual-specificity phosphatase, is overexpressed in 50% of acute myelogenous leukemia (AML) and associated with poor survival. We found that stable expression of PRL-3 confers cytokine independence and growth advantage of AML cells. However, how PRL-3 mediates these functions in AML is not known. To comprehensively screen for PRL3-regulated proteins in AML, we performed SILAC-based quantitative proteomics analysis and discovered 398 significantly perturbed proteins after PRL-3 overexpression. We show that Leo1, a component of RNA polymerase II-associated factor (PAF) complex, is a novel and important mediator of PRL-3 oncogenic activities in AML. We described a novel mechanism where elevated PRL-3 protein increases JMJD2C histone demethylase occupancy on Leo1 promoter, thereby reducing the H3K9me3 repressive signals and promoting Leo1 gene expression. Furthermore, PRL-3 and Leo1 levels were positively associated in AML patient samples (N=24; P<0.01). On the other hand, inhibition of Leo1 reverses PRL-3 oncogenic phenotypes in AML. Loss of Leo1 leads to destabilization of the PAF complex and downregulation of SOX2 and SOX4, potent oncogenes in myeloid transformation. In conclusion, we identify an important and novel mechanism by which PRL-3 mediates its oncogenic function in AML.
authors.affiliation: Authors' Affiliations: Cancer Science Institute of Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore; Department of Biological Sciences, Nanyang Technological University; Institute of Molecular and Cell Biology (A*STAR); and Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore.
authors.forename: Phyllis S Y
authors.initials: PS
authors.lastname: Chong
authors.affiliation: Authors' Affiliations: Cancer Science Institute of Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore; Department of Biological Sciences, Nanyang Technological University; Institute of Molecular and Cell Biology (A*STAR); and Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore.
authors.forename: Jianbiao
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Authors' Affiliations: Cancer Science Institute of Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore; Department of Biological Sciences, Nanyang Technological University; Institute of Molecular and Cell Biology (A*STAR); and Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore.
authors.forename: Lip-Lee
authors.initials: LL
authors.lastname: Cheong
authors.affiliation: Authors' Affiliations: Cancer Science Institute of Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore; Department of Biological Sciences, Nanyang Technological University; Institute of Molecular and Cell Biology (A*STAR); and Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore.
authors.forename: Shaw-Cheng
authors.initials: SC
authors.lastname: Liu
authors.affiliation: Authors' Affiliations: Cancer Science Institute of Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore; Department of Biological Sciences, Nanyang Technological University; Institute of Molecular and Cell Biology (A*STAR); and Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore.
authors.forename: Jingru
authors.initials: J
authors.lastname: Qian
authors.affiliation: Authors' Affiliations: Cancer Science Institute of Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore; Department of Biological Sciences, Nanyang Technological University; Institute of Molecular and Cell Biology (A*STAR); and Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore.
authors.forename: Tiannan
authors.initials: T
authors.lastname: Guo
authors.affiliation: Authors' Affiliations: Cancer Science Institute of Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore; Department of Biological Sciences, Nanyang Technological University; Institute of Molecular and Cell Biology (A*STAR); and Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore.
authors.forename: Siu Kwan
authors.initials: SK
authors.lastname: Sze
authors.affiliation: Authors' Affiliations: Cancer Science Institute of Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore; Department of Biological Sciences, Nanyang Technological University; Institute of Molecular and Cell Biology (A*STAR); and Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zeng
authors.affiliation: Authors' Affiliations: Cancer Science Institute of Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore; Department of Biological Sciences, Nanyang Technological University; Institute of Molecular and Cell Biology (A*STAR); and Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, SingaporeAuthors' Affiliations: Cancer Science Institute of Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore; Department of Biological Sciences, Nanyang Technological University; Institute of Molecular and Cell Biology (A*STAR); and Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, SingaporeAuthors' Affiliations: Cancer Science Institute of Singapore; Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore; Department of Biological Sciences, Nanyang Technological University; Institute of Molecular and Cell Biology (A*STAR); and Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore mdccwj@nus.edu.sg.
authors.forename: Wee Joo
authors.initials: WJ
authors.lastname: Chng
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D057809:HEK293 Cells; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000235:genetics / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism*; D009857:Oncogenes; D011401:Promoter Regions, Genetic; D017027:Protein Tyrosine Phosphatases / Q000235:genetics* / Q000378:metabolism*; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism; D055751:SOXC Transcription Factors / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D006657:Histones; C413655:KDM4C protein, human; C506154:LEO1 protein, human; D009363:Neoplasm Proteins; C527782:SOX2 protein, human; C083431:SOX4 protein, human; D055748:SOXB1 Transcription Factors; D055751:SOXC Transcription Factors; D014157:Transcription Factors; D056466:Histone Demethylases; D056484:Jumonji Domain-Containing Histone Demethylases; C484730:PTP4A3 protein, human; D017027:Protein Tyrosine Phosphatases