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

Abstract

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.

The Gentle Side of the UPS: Ubiquitin-Proteasome System and the Regulation of the Myogenic Program

“…Interestingly, tight control of p53 levels in muscle progenitors is pivotal for the regulation of differentiation and return to quiescence ( Flamini et al, 2018 ), leaving open the question regarding USP7’s role during this process. USP7 can also regulate gene expression through its interactions with Polycomb Repressor Complex (PRC) components and other epigenetic regulators ( Inoue et al, 2015 ; Lecona et al, 2015 ; Yamaguchi et al, 2017 ; Maat et al, 2021 ). Thus, it is possible to speculate that USP7 promotes differentiation by 1) controlling p53 levels, 2) interacting with specific transcriptional regulators such as Myogenin, and 3) by stablishing a favorable epigenetic landscape for the muscle genetic program.…”

Transcription Factors, R-Loops and Deubiquitinating Enzymes: Emerging Targets in Myelodysplastic Syndromes and Acute Myeloid Leukemia

“…Meanwhile, a proteomic study reported USP7 as a stable interactor of the Polycomb repressive complex PRC1.1. Notably, USP7 inhibitors strongly inhibited AML cell lines and primary AML cells proliferation in vitro, also independently of TP53 status, and significantly delayed leukemia development in a human MLL-AF9 xenograft mouse model [296].…”

“…As mentioned above, the critical cellular roles of USP7 and the effects of first-generation USP7 inhibitors in MDS/AML cellular models [263][264][265] support further research. Promisingly, the novel and more specific USP7 inhibitor FT671 was highly effective in impairing the growth of primary AML cells [296].…”

Roles of Polycomb complexes in regulating gene expression and chromatin structure in plants

“…the histone deacetylases HDAC1 and HDAC2 and the H3K36me2 demethylase KDM2B), and proteins that regulate PRC1 activity (e.g. the ubiquitin C-terminal hydrolase ubiquitin-specific protease 7 [USP7] that prevents self-ubiquitination of RING1 and PCGF to stabilize the complex and thus regulates H2A monoubiquitination levels [ de Bie et al., 2010 ; Maertens et al., 2010 ; Hu et al., 2014 ; Maat et al., 2021 ]) ( Figure 1 ).…”