Ubiquitin-specific protease 7 (USP7): an emerging drug target for cancer treatment

ABSTRACTIntroduction Ubiquitin-specific protease 7 (USP7) also known as herpesvirus-associated ubiquitin-specific protease (HAUSP) is a well-characterized cysteine protease that belongs to the largest subfamily of deubiquitinating enzymes (DUBs). It is involved in multiple signaling pathways, some of them dysregulated in malignant tumors. USP7 inhibition can lead to cell growth arrest and apoptosis through inhibition of tumor promoters and stabilization of tumor suppressors, making it a promising druggable target for cancer therapy.Areas covered This review covers the structure of USP7, its function in multiple signaling pathways and relevance in cancer, as well as recent advances and future perspectives in the development of USP7 inhibitors for cancer therapy.Expert opinion Literature reports display the multiple antitumor activities of USP7 inhibitors, both in vitro and in vivo. Nonetheless, none have entered clinical trials so far, highlighting the need to delve into a deeper understanding of USP7 binding sites and the development of more accurate compound screening methods. Despite these challenges, further development of USP7 inhibitors is promising as a valuable new approach for cancer treatment, including the ability to address chemoresistance.KEYWORDS: Cancerdeubiquitinasesdrug targetinhibitorsubiquitin-proteasome systemubiquitin-specific protease 7chemoresistance Article highlights USP7 is a key regulator of a myriad of cellular pathways including MDM2/MDMDX-p53, PTEN, Wnt/β-catenin and NF-κB.The abnormal expression of USP7 in many cancer types and its involvement in cancer-associated pathways make it a promising predictive biomarker and a target for pharmacological intervention.The combination of USP7 inhibitors and other cytotoxic agents may be a valuable approach to overcome drug resistance in some cancers.Some USP7 inhibitors exhibit anticancer effects by boosting anti-tumor immune responses.Although USP7 inhibitors show great anticancer potential both in vivo and in vitro, some challenges still need be overcome en route to clinical approval.List of abbreviations Akt=protein kinase BAsn=asparagineAsp=aspartateCID=β-catenin inhibitory domainCRC=colorectal cancerCys=cysteineDAXX=death domain associated proteinDUB=deubiquitinaseE1=ubiquitin-activating enzymeE2=ubiquitin-conjugating enzymeE3=ubiquitin-ligase enzymeFOXP3=forkhead box P3HAUSP=herpesvirus-associated ubiquitin-specific proteaseHDM2=human double minute 2His=histidineIκB=inhibitor of NF-κBMDM2=murine double minute 2MDMX=murine double minute XMM=multiple myelomamTor=mammalian target of rapamycinNEK2=NIMA related kinase 2NF-κB=nuclear factor-kappa BPARP=poly (ADP-ribose) polymerasePD-1=programmed cell death 1PD-L1=programmed cell death ligand 1PI3K=phosphatidylinositol 3-kinasePROTAC=proteolysis targeting chimeraPTEN=phosphatase and tensin homolog deleted on chromosome 10PTM=post-translation modificationRNF=ring finger proteinTeff cells=effector T cellsTRAF=tumor necrosis factor receptor-associated factorTreg cells=regulatory T cellsUBL=ubiquitin-like domainUPS=ubiquitin-proteasome systemUSP=ubiquitin-specific proteaseUSP7=ubiquitin-specific protease 7Declarations of interestLD Carreira thanks the Portuguese Research Agency FCT – Fundação para a Ciência e a Tecnologia, I.P., for funding the individual PhD grant 2022.10811.BD.RI Oliveira thanks the Portuguese Research Agency FCT – Fundação para a Ciência e a Tecnologia, I.P. for funding the individual PhD grant 2021.07538.BD.The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.Reviewer disclosuresA reviewer on this manuscript has disclosed that they have worked with Forma Therapeutics on USP7 inhibitors. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.Additional informationFundingThis paper was supported by the Portuguese Research Agency FCT—Fundação para a Ciência e a Tecnologia, I.P.