title: RUNX3 is oncogenic in natural killer/T-cell lymphoma and is transcriptionally regulated by MYC.
abstract: RUNX3, runt-domain transcription factor, is a master regulator of gene expression in major developmental pathways. It acts as a tumor suppressor in many cancers but is oncogenic in certain tumors. We observed upregulation of RUNX3 mRNA and protein expression in nasal-type extranodal natural killer (NK)/T-cell lymphoma (NKTL) patient samples and NKTL cell lines compared to normal NK cells. RUNX3 silenced NKTL cells showed increased apoptosis and reduced cell proliferation. Potential binding sites for MYC were identified in the RUNX3 enhancer region. Chromatin immunoprecipitation-quantitative PCR revealed binding activity between MYC and RUNX3. Co-transfection of the MYC expression vector with RUNX3 enhancer reporter plasmid resulted in activation of RUNX3 enhancer indicating that MYC positively regulates RUNX3 transcription in NKTL cell lines. Treatment with a small-molecule MYC inhibitor (JQ1) caused significant downregulation of MYC and RUNX3, leading to apoptosis in NKTL cells. The growth inhibition resulting from depletion of MYC by JQ1 was rescued by ectopic MYC expression. In summary, our study identified RUNX3 overexpression in NKTL with functional oncogenic properties. We further delineate that MYC may be an important upstream driver of RUNX3 upregulation and since MYC is upregulated in NKTL, further study on the employment of MYC inhibition as a therapeutic strategy is warranted.
authors.affiliation: Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: V
authors.identifier: 0000-0002-6017-3902
authors.initials: V
authors.lastname: Selvarajan
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.|International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Osato
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: G S S
authors.initials: GSS
authors.lastname: Nah
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: J
authors.initials: J
authors.lastname: Yan
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: T-H
authors.initials: TH
authors.lastname: Chung
authors.affiliation: Institute for Frontier Science Initiative, Kanazawa University, Japan.|Division of Genetics, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
authors.forename: D C-C
authors.initials: DC
authors.lastname: Voon
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Y
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Department of Anatomical Pathology, Faculty of Medicine, University of Indonesia, West Java, Indonesia.
authors.forename: M F
authors.initials: MF
authors.lastname: Ham
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.|School of Medicine, Dentistry and Biomedical Sciences, Queen's University Belfast, Belfast, UK.
authors.forename: M
authors.initials: M
authors.lastname: Salto-Tellez
authors.affiliation: Department of Virology, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Shimizu
authors.affiliation: Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: S-N
authors.initials: SN
authors.lastname: Choo
authors.affiliation: Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: S
authors.initials: S
authors.lastname: Fan
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore.|Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore.
authors.forename: W-J
authors.initials: WJ
authors.lastname: Chng
authors.affiliation: Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.|Cancer Science Institute of Singapore, National University of Singapore, Singapore.|Department of Pathology, National University Hospital, National University Health System, Singapore.
authors.forename: S-B
authors.initials: SB
authors.lastname: Ng
mesh_terms: D017209:Apoptosis; D001381:Azepines / Q000494:pharmacology; D001665:Binding Sites; D002455:Cell Division; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D050677:Core Binding Factor Alpha 3 Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D004742:Enhancer Elements, Genetic; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D005822:Genetic Vectors; D006801:Humans; D054391:Lymphoma, Extranodal NK-T-Cell / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D058990:Molecular Targeted Therapy; D009669:Nose Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D025941:Protein Interaction Mapping; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000502:physiology*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014158:Transcription, Genetic / Q000235:genetics*; D014230:Triazoles / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: C561695:(+)-JQ1 compound; D001381:Azepines; D050677:Core Binding Factor Alpha 3 Subunit; C489427:MYC protein, human; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; D011993:Recombinant Fusion Proteins; C493729:Runx3 protein, human; D014230:Triazoles