Blockade of the ubiquitin protease UBP43 destabilizes transcription factor PML/RARa and inhibits the growth of acute promyelocytic leukemia

Yongli Guo, Andrey V. Dolinko, Fadzai Chinyengetere, Bruce Stanton, Jennifer M. Bomberger, Eugene Demidenko, Da Cheng Zhou, Robert Gallagher, Tian Ma, Fabrizio Galimberti, Xi Liu, David Sekula, Sarah Freemantle, Ethan Dmitrovsky

Research output: Contribution to journalArticle

Abstract

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/RARa 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.

Original languageEnglish (US)
Pages (from-to)9875-9885
Number of pages11
JournalCancer Research
Volume70
Issue number23
DOIs
StatePublished - Dec 1 2010

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Guo, Y., Dolinko, A. V., Chinyengetere, F., Stanton, B., Bomberger, J. M., Demidenko, E., Zhou, D. C., Gallagher, R., Ma, T., Galimberti, F., Liu, X., Sekula, D., Freemantle, S., & Dmitrovsky, E. (2010). Blockade of the ubiquitin protease UBP43 destabilizes transcription factor PML/RARa and inhibits the growth of acute promyelocytic leukemia. Cancer Research, 70(23), 9875-9885. https://doi.org/10.1158/0008-5472.CAN-10-1100