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

Henny Maat; Tjerk Jan Atsma; Shanna M Hogeling; Aida Rodríguez López; Jennifer Jaques; Mirjam Olthuis; Marcel P de Vries; Chantal Gravesteijn; Annet Z Brouwers-Vos; Nisha van der Meer; Suzan Datema; Jonas Salzbrunn; Gerwin Huls; Roy Baas; Joost H A Martens; Vincent van den Boom; Jan Jacob Schuringa

doi:10.1016/j.isci.2021.102435

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

iScience. 2021 Apr 16;24(5):102435. doi: 10.1016/j.isci.2021.102435. eCollection 2021 May 21.

Authors

Henny Maat¹, Tjerk Jan Atsma¹, Shanna M Hogeling¹, Aida Rodríguez López¹, Jennifer Jaques¹, Mirjam Olthuis¹, Marcel P de Vries^{2

3}, Chantal Gravesteijn¹, Annet Z Brouwers-Vos¹, Nisha van der Meer¹, Suzan Datema¹, Jonas Salzbrunn¹, Gerwin Huls¹, Roy Baas⁴, Joost H A Martens⁵, Vincent van den Boom¹, Jan Jacob Schuringa¹

Affiliations

¹ Department of Experimental Hematology, Cancer Research Center Groningen, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
² Department of Pharmacy, Interfaculty Mass Spectrometry Center, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands.
³ Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
⁴ Division of Biochemistry and Oncode Institute, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.
⁵ Department of Molecular Biology, RIMLS, Radboud University, Nijmegen, The Netherlands.

Abstract

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.

Keywords: Cancer; Cell Biology; Molecular Biology.