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

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

SUBMITTER: Guo Y

PROVIDER: S-EPMC2999664 | biostudies-literature | 2010 Dec

REPOSITORIES: biostudies-literature

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

Guo Yongli Y Dolinko Andrey V AV Chinyengetere Fadzai F Stanton Bruce B Bomberger Jennifer M JM Demidenko Eugene E Zhou Da-Cheng DC Gallagher Robert R Ma Tian T Galimberti Fabrizio F Liu Xi X Sekula David D Freemantle Sarah S Dmitrovsky Ethan E

Cancer research 20101008 23

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 prot ...[more]

PMID: 20935222

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Project description:Dysregulation of PML, a significant tumor suppressor is linked with cancers of different histological origins, with a decreased expression observed with a higher tumor grade. This necessitates studying the mechanisms to maintain a stable expression of PML. However much less is known about the transcriptional regulation of PML, more so in the context of breast carcinoma. ERβ has emerged as a critical factor in understanding breast cancer, especially since a huge proportion of breast cancers are ERα- and thus insensitive to tamoxifen therapy. This study aims to uncover an unidentified mechanism of PML gene regulation and its stabilization in breast cancer via ERβ signalling and the impact on cellular apoptosis. We found that clinical expression of PML positively correlates with that of ERβ both in normal and breast carcinoma samples and inversely correlates with markers of cellular proliferation, hinting towards a possible mechanistic interdependence. Both mRNA and protein expression of PML were increased in response to ERβ overexpression on multiple human breast cancer cell lines. Mechanistically, luciferase reporter assays and chromatin-immunoprecipitation assays demonstrated that ERβ can interact with the PML promoter via ERE and AP1 sites to enhance its transcription. ERβ induced stable PML expression causes a decline of its target protein Survivin and simultaneously provides a stable docking platform leading to stabilisation of its target Foxo3a, further causing transcriptional upregulation of pro-apoptotic factors p21 and p27. Immunohistochemical analyses of cancer and normal breast tissues and functional assays conducted corroborated the findings. Collectively, our study identifies ERβ signalling as a novel mechanism for PML gene regulation in ERα- breast cancer. It also reveals bi-directional downstream effect in which 'ERβ-PML-(Foxo3a/Survivin)' network acts as a therapeutic axis by suppressing cellular survival and promoting cellular apoptosis in breast carcinoma.

Dataset Information

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

Publications

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

Similar Datasets

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