We showed that knockdown of USP7 or treatment with USP7 inhibitor P5091 suppressed liver cancer growth by promoting CD8+ T cell activity in Hepa1-6 xenograft mice and in HepG2 or Huh7 cells co-cultured with T cells, whereas USP7 overexpression produced the opposite effect...In an immunocompetent liver cancer mouse model, the dual blockade of USP7 and LAG3 resulted in a superior antitumor activity compared with anti-LAG3 therapy alone. We conclude that USP7 diminishes CD8+ T cell activity by a USP7/PRDM1 positive feedback loop on FGL1 production in liver cancer; USP7 might be a promising target for liver cancer immunotherapy.

However, the chemoresistance of cancer cells to USP7i (P22077 and P5091) and mechanisms to overcome it have not yet been investigated. Inhibition of HSF1 and PERK significantly sensitized cancer cells to USP7i-induced cytotoxicity. Our study demonstrated that the ER stress-PERK axis is responsible for chemoresistance to USP7i, and inhibiting PERK is a potential strategy for improving the anticancer efficacy of USP7i.

Mechanistically, the administration of p22077 alleviated Ang II-induced activation of TGF-β/Smad2, NF-κB/NLRP3, NADPH oxidases (NOX2 and NOX4) signals, the up-regulation of CX43, ox-CaMKII, CaMKII, Kir2.1, and down-regulation of SERCA2a. Together, this study, for the first time, suggests that USP7 is a critical driver of AF and revealing USP7 may present a new target for atrial fibrillation therapeutic strategies.

Gain-of-function and loss-of-function assays were conducted in SK-Hep1 and HepG2 cells transfected with USP7 overexpression/knockdown plasmids and USP7 inhibitor P22077...Overexpression of BTF3 partially rescue the inhibitory effects of USP7 depletion on the malignant phenotypes and stemness properties of SK-Hep1 and HepG2 cells. USP7 can promote the stemness and malignant phenotype of HCC by stabilizing BTF3.

Mechanistically, USP47 prevented YTHDF1 ubiquitination to attenuate the association of YTHDF1 with translation initiation machinery, thereby decreasing m6A-based c-Myc translation efficiency. Our findings reveal that USP47 directs m6A-dependent metabolic programs to orchestrate Treg cell homeostasis and suggest novel approaches for selective immune modulation in cancer and autoimmune diseases by targeting USP47.

The above risk score and nomogram can accurately predict prognosis in ESCC patients and provide guidance for chemotherapy and immunotherapy.

Treatment of the CLL cell line MEC1 and primary CLL patient samples with DUB inhibitors including PR-619 (pan-DUBi), P5091 (USP7i) and HBX19818 (USP7i) alone reduces the phosphorylation of AKTS437 and FOXO1T24, indicating that DUBs play a role in inhibiting FOXO1 activity. Additionally, FOXO1 activity studies demonstrated significant activation of FOXO1 upon ibrutinib treatment, which was further enhanced in the USP7 KD and combination with USP7i. These studies suggest that selective DUBs play a role in BCR-mediated signalling to aid in the promotion of CLL cell survival and chemo-resistance through FOXO1 inhibition, and targeting these DUBs enhance FOXO1 activity leading to cell cycle arrest and apoptosis.

Pharmacological inhibition of USP7 by P5091 phenocopies the shUSP7-induced senescent phenotype. We show that the bifunctional histone deacetylase (HDAC)/LSD1 inhibitor domatinostat has an additive antitumor effect, eliminating P5091-induced senescent cells, paving the way to a therapeutic combination for individuals with melanoma.

Although EZH2 kinase inhibitors, such as EPZ-6438, provide clinical benefit, certain cancer cells are resistant to the enzymatic inhibition of EZH2 because of the inability to functionally target mutant EZH2, or because of cells' dependence on the non-histone methyltransferase activity of EZH2...Moreover, targeting of USP47 leads to death of mutant EZH2-positive cells in vitro and in vivo. Taken together, we propose targeting USP47 with a small molecule inhibitor as a novel potential therapy for DLBCL and other hematologic malignancies characterized by mutant EZH2 expression.

Finally, the expression of miR-101-3p is downregulated in lung cancer patients, and the patients with low miR-101-3p expression exhibit a lower survival rate, indicating that miR-101-3p is associated with tumorigenesis. Together, our findings suggest that miR-101-3p functions as a tumor suppressor by targeting USP47 and could be a potential therapeutic target for cancers.

Further analysis showed that the level of pro-apoptotic Bax was regulated by TCEA3. These results indicated that the USP47-TCEA3 axis modulates cell pyroptosis and apoptosis and may serve as a target for therapeutic intervention in CRC.

PTL diminishes CCSCs self-renewal and induces apoptosis of CCSCs. Taken together, our findings highlighted a novel DUB involved in the modulation of CCSCs stemness and the potential of PTL in the CRC treatment by targeting CCSCs as the USP47 inhibitor.

Furthermore, compared with the shNC group, KCNQ1OT1 knockdown significantly downregulated USP47 expression, which was significantly counteracted by miR‑454 knockdown. Collectively, the results of the present study indicated that KCNQ1OT1 enhanced DDP resistance in NPC cells via the miR‑454/USP47 axis, suggesting a potential therapeutic target for patients with DDP‑resistant NPC.

E2F7 silencing reduced the production of ALDH1 and CD133 colon cancer stem cells and antagonized the effects of 5-fluorouracil (5-FU) treatment. Besides, the silencing of E2F7 was observed to suppress the oxidative stress, proliferation, migration, as well as invasion of ALDH1 cells in vitro and tumorigenesis of colon cancer cells in vivo. Our findings reveal the pro-oncogenic effect of E2F7 on colon cancer development, highlighting E2F7 as a novel target for therapeutic strategy for colon cancer.

Functional analysis shows that USP47 knockdown represses proliferation of CML cells sensitive or resistant to imatinib in vitro and in vivo...Moreover, P22077 eliminates leukemia stem/progenitor cells in CML mice. Together, targeting USP47 is a promising strategy to overcome TKI resistance and eradicate leukemia stem/progenitor cells in CML.

Moreover, combined treatment with the USP7-specific inhibitor P5091 and EZH2 inhibitors, such as GSK126, EPZ6438, and DZNep, induced synergistic inhibitory effects on cell migration, invasion, and sphere-forming potential in prostate cancer cells. Collectively, our findings revealed that the promotion of the malignancy-associated characteristics of prostate cancer cells by USP7 was in part due to EZH2 stabilization. Thus, we suggest that simultaneous treatment with a USP7 inhibitor and an EZH2 inhibitor could be a rational strategy for treating EZH2-dependent cancers.

Finally, we found that AKT/mTOR signal pathway might be a possible principle in mediating DSCAM-AS1 in OS. Taken together, DSCAM-AS1 accelerated OS progression via miR-101-3p/USP47 axis, which might present a new potential therapeutic treatment for OS.

Genetic knockdown or pharmacological inhibition (P5091 or P22027) of USP7 reduced the proliferation rate of lung cancer cells and decreased the capacity of colony formation of lung cancer cells in vitro, whereas lung cancer cells growth inhibition by FTO knockdown is restored by overexertion of USP7. Collectively, our findings demonstrate that the m6A demethylase FTO promotes the growth of NSCLC cells by increasing the expression of USP7.

Kyoto Encyclopedia of Genes and Genomes analysis revealed that the enriched pathways in dysregulated proteins included the vascular endothelial growth factors (VEGF) signaling pathway, the mitogen-activated protein kinase (MAPK) signaling pathway, and the adipocytokine signaling pathway. The identification of proteins and pathways is crucial toward elucidating the radiation response process of the liver, which may facilitate the discovery of novel therapeutic targets.