Highlights in USP7 inhibitors for cancer treatment

Oliveira, Rita I.; Guedes, Romina A.; Salvador, Jorge A. R.

doi:10.3389/fchem.2022.1005727

Cited by 22 publications

(14 citation statements)

References 69 publications

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“…Our studies indicated an accumulation of USP7 in the nucleus during the proangiogenic function of ACEI in ECs, where it binds to Sp1/Sp3 and protects Sp1/Sp3 from proteasomal degradation. Furthermore, USP7 inhibitor significantly abrogated the proangiogenic function of ACEI, indicating the adverse effect of potential drug aiming at USP7 61 . Phosphorylation of the Ser18 site by the kinase CK2 stabilizes USP7, thus contributing to the downstream stability of MDM2 in the nucleus 36 .…”

Section: Discussionmentioning

confidence: 97%

Angiotensin-converting enzyme inhibitor promotes angiogenesis through Sp1/Sp3-mediated inhibition of notch signaling in male mice

Yuan

et al. 2023

Nat Commun

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Angiogenesis is a critical pathophysiological process involved in organ growth and various diseases. Transcription factors Sp1/Sp3 are necessary for fetal development and tumor growth. Sp1/Sp3 proteins were downregulated in the capillaries of the gastrocnemius in patients with critical limb ischemia samples. Endothelial-specific Sp1/Sp3 knockout reduces angiogenesis in retinal, pathological, and tumor models and induced activation of the Notch1 pathway. Further, the inactivation of VEGFR2 signaling by Notch1 contributes to the delayed angiogenesis phenotype. Mechanistically, endothelial Sp1 binds to the promoter of Notch1 and inhibits its transcription, which is enhanced by Sp3. The proangiogenic effect of ACEI is abolished in Sp1/Sp3-deletion male mice. We identify USP7 as an ACEI-activated deubiquitinating enzyme that translocated into the nucleus binding to Sp1/Sp3, which are deacetylated by HDAC1. Our findings demonstrate a central role for endothelial USP7-Sp1/Sp3-Notch1 signaling in pathophysiological angiogenesis in response to ACEI treatment.

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Section: Discussionmentioning

confidence: 97%

Angiotensin-converting enzyme inhibitor promotes angiogenesis through Sp1/Sp3-mediated inhibition of notch signaling in male mice

Yuan

et al. 2023

Nat Commun

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“…Targeting the critical role of TOPORS in STUbL-driven cellular responses might provide a more specific and thus less toxic alternative to full inhibition of SUMOylation in some clinical contexts. In this regard, harnessing the notion that USP7 inhibitors, several of which display efficacy for cancer therapy in pre-clinical studies 56 , potently deplete TOPORS and recapitulate the consequences of TOPORS loss may be particularly useful. Further studies of the mechanisms of TOPORS STUbL function and how this may be exploited therapeutically are therefore well warranted.…”

Section: Discussionmentioning

confidence: 99%

Concerted SUMO-targeted ubiquitin ligase activities of TOPORS and RNF4 are essential for stress management and cell proliferation

Liu,

Ackermann,

Hoffmann

et al. 2023

Preprint

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SummaryProtein SUMOylation provides a principal driving force for cellular stress responses including DNA-protein crosslink (DPC) repair and arsenic-induced PML body degradation. In genome-scale screens, we identified the human E3 ligase TOPORS as a key effector of SUMO-dependent DPC resolution. We demonstrate that TOPORS promotes DPC repair by functioning as a SUMO-targeted ubiquitin ligase (STUbL) for DPCs, combining ubiquitin ligase activity through its RING domain with poly-SUMO chain binding via a cluster of SUMO-interacting motifs, analogous to the STUbL RNF4. Surprisingly, the STUbL activities of TOPORS and RNF4 are both required for SUMO-dependent DPC repair, PML degradation and other stress responses, making overlapping and distinct contributions to ubiquitin chain formation on SUMOylated targets to enable p97/VCP unfoldase recruitment. Combined loss of TOPORS and RNF4 is synthetic lethal even in unstressed cells, leading to defective clearance of SUMOylated proteins from chromatin accompanied by cell cycle arrest and apoptosis. Together, our findings establish TOPORS as a novel STUbL whose concerted action with RNF4 defines a general mechanistic principle in crucial cellular processes governed by direct SUMO-ubiquitin crosstalk.HighlightsThe RING E3 ligase TOPORS is required for SUMO-dependent DPC repairTOPORS is a novel SUMO-targeted ubiquitin ligase (STUbL)TOPORS promotes multiple STUbL-driven processes in conjunction with RNF4Combined TOPORS and RNF4 loss is synthetic lethal in human cells

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“…Indeed, the increased mechanistic and structural characterisation of DUBs/ULPs with their targets or inhibitors, combined with deep sequencing of patient samples, either at the genomic or expression level, will likely enable more precise patient stratification with reduced likelihood of developing resistance. Current efforts to inhibit DUBs/ULPs are reviewed elsewhere in more detail [ 53 , 142 , 316–318 ]. Overall, an enhanced understanding of Ub/UBL signalling via DUBs and ULPs in DDR signalling will provide a stable grounding to develop targeted strategies for treating human diseases, such as cancers.…”

Section: Conclusion and Future Perspectivesmentioning

confidence: 99%

DoUBLing up: ubiquitin and ubiquitin-like proteases in genome stability

Foster,

Wang,

Schmidt

2024

Biochemical Journal

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Maintaining stability of the genome requires dedicated DNA repair and signalling processes that are essential for the faithful duplication and propagation of chromosomes. These DNA damage response (DDR) mechanisms counteract the potentially mutagenic impact of daily genotoxic stresses from both exogenous and endogenous sources. Inherent to these DNA repair pathways is the activity of protein factors that instigate repair processes in response to DNA lesions. The regulation, coordination, and orchestration of these DDR factors is carried out, in a large part, by post-translational modifications, such as phosphorylation, ubiquitylation, and modification with ubiquitin-like proteins (UBLs). The importance of ubiquitylation and UBLylation with SUMO in DNA repair is well established, with the modified targets and downstream signalling consequences relatively well characterised. However, the role of dedicated erasers for ubiquitin and UBLs, known as deubiquitylases (DUBs) and ubiquitin-like proteases (ULPs) respectively, in genome stability is less well established, particularly for emerging UBLs such as ISG15 and UFM1. In this review, we provide an overview of the known regulatory roles and mechanisms of DUBs and ULPs involved in genome stability pathways. Expanding our understanding of the molecular agents and mechanisms underlying the removal of ubiquitin and UBL modifications will be fundamental for progressing our knowledge of the DDR and likely provide new therapeutic avenues for relevant human diseases, such as cancer.

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Highlights in USP7 inhibitors for cancer treatment

Cited by 22 publications

References 69 publications

Angiotensin-converting enzyme inhibitor promotes angiogenesis through Sp1/Sp3-mediated inhibition of notch signaling in male mice

Angiotensin-converting enzyme inhibitor promotes angiogenesis through Sp1/Sp3-mediated inhibition of notch signaling in male mice

Concerted SUMO-targeted ubiquitin ligase activities of TOPORS and RNF4 are essential for stress management and cell proliferation

DoUBLing up: ubiquitin and ubiquitin-like proteases in genome stability

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