title: SUMOylation of HMGA2: selective destabilization of promyelocytic leukemia protein via proteasome.
abstract: The HMGA2 architectural protein functions in a variety of cellular processes, such as cell growth, transcription regulation, neoplastic transformation, and progression. Up-regulation of HMGA2 protein is observed in many tumors and is associated with advanced cancers with poor prognoses. Although the expression and biochemical properties of HMGA2 protein are regulated by microRNA and phosphorylation, it is unknown whether HMGA2 activity can also be regulated by SUMOylation, and that is what is investigated in this report. We identified HMGA2 as a SUMOylation target and showed that the expression of wild-type HMGA2, but not SUMOylation-defective HMGA2(2K/R), selectively lowered the steady-state level of PML protein. Consequently, the HMGA2-elicited PML down-regulation rendered a reduction in the average number of PML nuclear bodies per cell and the volume of PML assembled per PML nuclear body. Using small interfering RNA to suppress endogenous ubiquitin expression and proteasome inhibitor to repress ubiquitin-mediated protein degradation, we showed that HMGA2 confers PML down-regulation through ubiquitin-proteasome-dependent protein degradation. Importantly, arsenic trioxide treatment stimulated HMGA2 SUMOylation, leading to the formation of HMGA2 nuclear foci surrounding PML nuclear bodies and the stimulation of PML degradation. Collectively, our results unveil a previously unrecognized effect by HMGA2 on the modulation of PML protein level, providing a novel mechanism underlying HMGA2 function and underscoring the molecular basis for oncogenic progression by HMGA2.
authors.affiliation: Department of Pharmacology and Pharmaceutical Sciences, University of Southern California, Los Angeles, California, USA.
authors.forename: Xuefei
authors.initials: X
authors.lastname: Cao
authors.forename: Carlos
authors.initials: C
authors.lastname: Clavijo
authors.forename: Xu
authors.initials: X
authors.lastname: Li
authors.forename: H Helen
authors.initials: HH
authors.lastname: Lin
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.forename: Hsiu-Ming
authors.initials: HM
authors.lastname: Shih
authors.forename: David K
authors.initials: DK
authors.lastname: Ann
mesh_terms: D000818:Animals; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D015153:Blotting, Western; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism*; D002522:Chlorocebus aethiops; D015536:Down-Regulation; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005453:Fluorescence; D005455:Fluorescent Antibody Technique; D049452:Green Fluorescent Proteins; D025743:HMGA2 Protein / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010087:Oxides / Q000494:pharmacology; D010306:Parotid Gland / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D000071156:Promyelocytic Leukemia Protein; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D025842:SUMO-1 Protein / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D044763:Ubiquitin-Conjugating Enzymes; D016335:Zinc Fingers; D000098843:Ubiquitin-Conjugating Enzyme UBC9
chemical_list: D001152:Arsenicals; D025743:HMGA2 Protein; D009687:Nuclear Proteins; D010087:Oxides; D000071156:Promyelocytic Leukemia Protein; D034741:RNA, Small Interfering; D025842:SUMO-1 Protein; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; C485184:enhanced green fluorescent protein; C070576:PML protein, human; D049452:Green Fluorescent Proteins; D044763:Ubiquitin-Conjugating Enzymes; D046988:Proteasome Endopeptidase Complex; D000098843:Ubiquitin-Conjugating Enzyme UBC9; D000077237:Arsenic Trioxide