title: SUMO1 negatively regulates the transcriptional activity of EVI1 and significantly increases its co-localization with EVI1 after treatment with arsenic trioxide.
abstract: Aberrant expression of the proto-oncogene EVI1 (ecotropic virus integration site1) has been implicated not only in myeloid or lymphoid malignancies but also in colon, ovarian and breast cancers. Despite its importance in oncogenesis, the regulatory factors and mechanisms that potentiate the function of EVI1 and its consequences are partially known. Here we demonstrated that EVI1 is post-translationally modified by SUMO1 at lysine residues 533, 698 and 874. Although both EVI1 and SUMO1 were found to co-localize in nuclear speckles, the sumoylation mutant of EVI1 failed to co-localize with SUMO1. Sumoylation abrogated the DNA binding efficiency of EVI1 and also affected EVI1 mediated transactivation. The SUMO ligase PIASy was found to play a bi-directional role on EVI1, PIASy enhanced EVI1 sumoylation and augmented sumoylated EVI1 mediated repression. PIASy was also found to interact with EVI1 and impaired EVI1 transcriptional activity independent of its ligase activity. Arsenic trioxide (ATO) known to act as an antileukemic agent for acute promyelocytic leukemia (APL) not only enhanced EVI1 sumoylation but also enhanced the co-localization of EVI1 and SUMO1 in nuclear bodies distinct from PML nuclear bodies. ATO treatment also affected the Bcl-xL protein expression in EVI1 positive cell line. Thus, the results showed that arsenic treatment enhanced EVI1 sumoylation, deregulated Bcl-xL, which eventually may induce apoptosis in EVI1 positive cancer cells. The study for the first time explores and reports sumoylation of EVI1, which plays an essential role in regulating its function.
authors.affiliation: Department of Gene Function and Regulation, Institute of Life Sciences, Bhubaneswar, Orissa, India.
authors.forename: Sneha
authors.initials: S
authors.lastname: Singh
authors.forename: Anjan Kumar
authors.initials: AK
authors.lastname: Pradhan
authors.forename: Soumen
authors.initials: S
authors.lastname: Chakraborty
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D000074008:MDS1 and EVI1 Complex Locus Protein; D016297:Mutagenesis, Site-Directed; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D010087:Oxides / Q000494:pharmacology*; D000090063:Proto-Oncogene Mas; D011519:Proto-Oncogenes / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism*; D058207:Sumoylation; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D004268:DNA-Binding Proteins; C000715470:MAS1 protein, human; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; D010087:Oxides; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D025842:SUMO-1 Protein; C495501:SUMO1 protein, human; D014157:Transcription Factors; D051020:bcl-X Protein; D000077237:Arsenic Trioxide
keywords: Arsenic trioxide (ATO); Bcl-xL; EVI1; PIASy; SIRT1; Sumoylation