The USP7-TRIM27 axis mediates non-canonical PRC1.1 function and is a druggable target in leukemia

In an attempt to unravel functionality of the non-canonical PRC1.1 Polycomb complex in human leukemogenesis, we show that USP7 and TRIM27 are integral components of PRC1.1. USP7 interactome analyses show that PRC1.1 is the predominant Polycomb complex co-precipitating with USP7. USP7 inhibition resu...

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Published in:iScience 2021-05, Vol.24 (5), p.102435-102435, Article 102435
Main Authors: Maat, Henny, Atsma, Tjerk Jan, Hogeling, Shanna M., Rodríguez López, Aida, Jaques, Jennifer, Olthuis, Mirjam, de Vries, Marcel P., Gravesteijn, Chantal, Brouwers-Vos, Annet Z., van der Meer, Nisha, Datema, Suzan, Salzbrunn, Jonas, Huls, Gerwin, Baas, Roy, Martens, Joost H.A., van den Boom, Vincent, Schuringa, Jan Jacob
Format: Article
Language:English
Subjects:
Cancer
Cell Biology
Molecular Biology
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Summary:In an attempt to unravel functionality of the non-canonical PRC1.1 Polycomb complex in human leukemogenesis, we show that USP7 and TRIM27 are integral components of PRC1.1. USP7 interactome analyses show that PRC1.1 is the predominant Polycomb complex co-precipitating with USP7. USP7 inhibition results in PRC1.1 disassembly and loss of chromatin binding, coinciding with reduced H2AK119ub and H3K27ac levels and diminished gene transcription of active PRC1.1-controlled loci, whereas H2AK119ub marks are also lost at PRC1 loci. TRIM27 and USP7 are reciprocally required for incorporation into PRC1.1, and TRIM27 knockdown partially rescues USP7 inhibitor sensitivity. USP7 inhibitors effectively impair proliferation in AML cells in vitro, also independent of the USP7-MDM2-TP53 axis, and MLL-AF9-induced leukemia is delayed in vivo in human leukemia xenografts. We propose a model where USP7 counteracts TRIM27 E3 ligase activity, thereby maintaining PRC1.1 integrity and function. Moreover, USP7 inhibition may be a promising new strategy to treat AML patients. [Display omitted] •We identify USP7 and TRIM27 as integral components of non-canonical PRC1.1•USP7 inhibition results in PRC1.1 disassembly and loss of chromatin binding•TRIM27 and USP7 are reciprocally required for incorporation into PRC1.1•USP7 inhibitors effectively impair AML proliferation, also independent of TP53 Molecular Biology; Cell Biology; Cancer
ISSN:2589-0042
2589-0042
DOI:10.1016/j.isci.2021.102435