Blockade of the Ubiquitin Protease UBP43 Destabilizes Transcription Factor PML/RARα and Inhibits the Growth of Acute Promyelocytic Leukemia

• Published in: Cancer research (Chicago, Ill.) Vol. 70; no. 23; pp. 9875 - 9885
• Main Authors: YONGLI GUO, DOLINKO, Andrey V, XI LIU, SEKULA, David, FREEMANTLE, Sarah, DMITROVSKY, Ethan, CHINYENGETERE, Fadzai, STANTON, Bruce, BOMBERGER, Jennifer M, DEMIDENKO, Eugene, ZHOU, Da-Cheng, GALLAGHER, Robert, TIAN MA, GALIMBERTI, Fabrizio
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.12.2010
• Subjects: Animals; Antineoplastic agents; Apoptosis - drug effects; Biological and medical sciences; Cell Differentiation - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Chlorocebus aethiops; Chromosome aberrations; COS Cells; Endopeptidases - genetics; Endopeptidases - metabolism; Gene Expression Regulation, Neoplastic - drug effects; Hematologic and hematopoietic diseases; Humans; Immunoblotting; Leukemia, Promyelocytic, Acute - drug therapy; Leukemia, Promyelocytic, Acute - genetics; Leukemia, Promyelocytic, Acute - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Medical genetics; Medical sciences; Mice; Oncogene Proteins, Fusion - genetics; Oncogene Proteins, Fusion - metabolism; Pharmacology. Drug treatments; Reverse Transcriptase Polymerase Chain Reaction; RNA Interference; Tretinoin - pharmacology; Tumor Burden - drug effects; Tumors; Xenograft Model Antitumor Assays; Chromosomal aberration; Promyelocytic leukemia; Ubiquitin; Enzyme; Growth; Acute; Malignant hemopathy; Peptidases; Signal transduction; Abnormal chromosome; Hydrolases; Inhibitor; Transcription factor; Hybrid gene; Cancer; M3 acute myelocytic leukemia; Chromosome translocation
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-10-1100

More effective treatments for acute promyelocytic leukemia (APL) are needed. APL cell treatment with all-trans-retinoic acid (RA) degrades the chimeric, dominant-negative-acting transcription factor promyelocytic leukemia gene (PML)/RARα, which is generated in APL by chromosomal translocation. The E1-like ubiquitin-activating enzyme (UBE1L) associates with interferon-stimulated gene ISG15 that binds and represses PML/RARα protein. Ubiquitin protease UBP43/USP18 removes ISG15 from conjugated proteins. In this study, we explored how RA regulates UBP43 expression and the effects of UBP43 on PML/RARα stability and APL growth, apoptosis, or differentiation. RA treatment induced UBE1L, ISG15, and UBP43 expression in RA-sensitive but not RA-resistant APL cells. Similar in vivo findings were obtained in a transgenic mouse model of transplantable APL, and in the RA response of leukemic cells harvested directly from APL patients. UBP43 knockdown repressed PML/RARα protein levels and inhibited RA-sensitive or RA-resistant cell growth by destabilizing the PML domain of PML/RARα. This inhibitory effect promoted apoptosis but did not affect the RA differentiation response in these APL cells. In contrast, elevation of UBP43 expression stabilized PML/RARα protein and inhibited apoptosis. Taken together, our findings define the ubiquitin protease UBP43 as a novel candidate drug target for APL treatment.