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

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Guo Y, Dolinko AV, Chinyengetere F, Stanton B, Bomberger JM, Demidenko E, Zhou DC, Gallagher R, Ma T, Galimberti F, Liu X, Sekula D, Freemantle S, Dmitrovsky E

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

Cancer Res. 2010 Dec 1;70(23):9875-85. doi: 10.1158/0008-5472.CAN-10-1100. Epub 2010 Oct 8.

PubMed ID
20935222 [ View in PubMed
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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)/RARalpha, 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/RARalpha 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/RARalpha 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/RARalpha protein levels and inhibited RA-sensitive or RA-resistant cell growth by destabilizing the PML domain of PML/RARalpha. 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/RARalpha protein and inhibited apoptosis. Taken together, our findings define the ubiquitin protease UBP43 as a novel candidate drug target for APL treatment.