title: The SUMO E3-ligase PIAS1 regulates the tumor suppressor PML and its oncogenic counterpart PML-RARA.
abstract: The ubiquitin-like SUMO proteins covalently modify protein substrates and regulate their functional properties. In a broad spectrum of cancers, the tumor suppressor PML undergoes ubiquitin-mediated degradation primed by CK2 phosphorylation. Here, we report that the SUMO E3-ligase inhibitor PIAS1 regulates oncogenic signaling through its ability to sumoylate PML and the PML-RARA oncoprotein of acute promyelocytic leukemia (APL). PIAS1-mediated SUMOylation of PML promoted CK2 interaction and ubiquitin/proteasome-mediated degradation of PML, attenuating its tumor suppressor functions. In addition, PIAS1-mediated SUMOylation of PML-RARA was essential for induction of its degradation by arsenic trioxide, an effective APL treatment. Moreover, PIAS1 suppression abrogated the ability of arsenic trioxide to trigger apoptosis in APL cells. Lastly, PIAS1 was also essential for PML degradation in non-small cell lung carcinoma (NSCLC) cells, and PML and PIAS1 were inversely correlated in NSCLC cell lines and primary specimens. Together, our findings reveal novel roles for PIAS1 and the SUMOylation machinery in regulating oncogenic networks and the response to leukemia therapy.
authors.affiliation: Division of Hematology and Oncology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Rabellino
authors.forename: Brandon
authors.initials: B
authors.lastname: Carter
authors.forename: Georgia
authors.initials: G
authors.lastname: Konstantinidou
authors.forename: Shwu-Yuan
authors.initials: SY
authors.lastname: Wu
authors.forename: Alessandro
authors.initials: A
authors.lastname: Rimessi
authors.forename: Lauren A
authors.initials: LA
authors.lastname: Byers
authors.forename: John V
authors.initials: JV
authors.lastname: Heymach
authors.forename: Luc
authors.initials: L
authors.lastname: Girard
authors.forename: Cheng-Ming
authors.initials: CM
authors.lastname: Chiang
authors.forename: Julie
authors.initials: J
authors.lastname: Teruya-Feldstein
authors.forename: Pier Paolo
authors.initials: PP
authors.lastname: Scaglioni
mesh_terms: D000818:Animals; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D010087:Oxides / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide; D000071156:Promyelocytic Leukemia Protein; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D025841:Small Ubiquitin-Related Modifier Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D001152:Arsenicals; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D010087:Oxides; C106529:PIAS1 protein, human; D000071156:Promyelocytic Leukemia Protein; D050828:Protein Inhibitors of Activated STAT; D025841:Small Ubiquitin-Related Modifier Proteins; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D025801:Ubiquitin; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; C070576:PML protein, human; D000077237:Arsenic Trioxide