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PubMed2025

USP2 reversed cisplatin resistance through p53-mediated ferroptosis in NSCLC.

BACKGROUND: It has demonstrated the indispensable role of ferroptosis in conferring cisplatin resistance in non-small cell lung cancer (NSCLC), as well as the involvement of ubiquitin-specific protease (USP) in regulating ferroptosis. This paper aspired to the mechanism of USP2 and ferroptosis on NSCLC cisplatin resistance. METHODS: Ubiquitin-specific protease mRNA expression, was detected through RT-qPCR. In vitro functional assays assessed the effects of USP2 overexpression on DDP resistance, cell proliferation capability, and ferroptosis markers in A549/DDP and H1299/DDP cells. Ubiquitination assays evaluated the ubiquitination levels of p53 following USP2 overexpression. Co-immunoprecipitation (Co-IP) assays confirmed the binding relationship between USP2 and p53. In vivo experiments in mice explored the specific role of the USP2-p53 axis in a xenograft tumor model. RESULTS: USP2 expression was suppressed in cisplatin-resistant NSCLC cells. USP2 overexpression inhibited cell viability in cisplatin-resistant cells. Among the ferroptosis markers, the results showed that USP2 overexpression promoted LDH release, Fe2+ level, MDA and Lipid ROS, while inhibited GPX4 activity and GSH levels. The WB results revealed that USP2 overexpression inhibited GPX4, SLC7A11 and cytoplasm p53 protein expression, while promoted the nucleus p53 protein expression. Moreover, USP2 directly bound to p53 and USP2 overexpression stabilized p53 protein by suppressing its ubiquitination. In vivo experiments further suggest that the USP2-p53 pathway plays a crucial role in regulating cisplatin sensitivity in A549/DDP cells. CONCLUSION: USP2 acted on the K305R site of p53, which resulted in its deubiquitination. This cellular process could modulate cisplatin resistance through ferroptosis in NSCLC. This study could provide a potential therapeutic target to NSCLC.

Ferroptosis↗

PubMed2025

The downregulation of ubiquitin-specific peptidase 2 indicates a poor prognosis and promotes the progression of gastric cancer through focal adhesion and ECM pathway signaling.

Gastric cancer ranks among the most prevalent forms of cancer worldwide. Recent rapid advancements in diagnostic methods, neoadjuvant or adjuvant therapies, and surgical procedures have significantly improved survival rates for patients with gastric cancer. Nonetheless, these benefits have not yet reached the majority of individuals affected. Previous research has indicated that USP2, a component of the ubiquitin system, plays a crucial role in reshaping the proteome and enhancing the prognosis of diseases. However, the current understanding of USP2 expression and the associated pathways in gastric cancer remains unclear. The differential expression of USP2 was examined in pan-cancer, with a particular focus on its expression in gastric cancer cells and patients. Additionally, the impact of USP2 on the proliferation, migration, and apoptosis of gastric cancer cells was explored via CCK8, transwell, and invasion assays. RNA sequencing was employed to investigate pathways associated with USP2, and RT-qPCR and western blotting were utilized to confirm the expression of related pathway genes and proteins. The prognostic value of a model derived from USP2 expression was assessed and validated. USP2 expression was significantly reduced in gastric cancer cells and patient samples (p < 0.05). Patients with low USP2 expression are primarily associated with genetic variations, neoantigen loads, microsatellite instability (MSI) scores, and immune cell infiltration (p < 0.05). The overexpression of USP2 suppresses proliferation, migration, and cell cycle progression while enhancing apoptosis in GC cells. Concurrently, we identified 865 genes whose expression was downregulated. KEGG and GSEA enrichment analyses revealed significant suppression of the focal adhesion and ECM receptor interaction pathways following USP2 overexpression. A genomic model derived from USP2 was constructed and validated for its reliability in predicting patient prognosis. The expression of USP2 was positively correlated with sensitivity to small-molecule drugs, including entinostat, SB590885, and PF-562,271. USP2 acts as a negative regulator of gastric cancer progression. Consequently, USP2 has the potential to be utilized as a therapeutic target to improve the clinical prognosis and survival rates of patients.

Humans↗

PubMed2025

Deubiquitinase-dependent transcriptional silencing controls inflammation.

Transcriptional control is crucial for the regulation of inflammation. While it is well-established that inducible transcriptional repressors are synthesized de novo through signal-dependent transcriptional upregulation, it remains unclear whether post-translational modification mechanisms, such as deubiquitination, also contribute to this process. We previously identified developmentally silenced sine oculis (SIX) transcription factors that are reactivated to control inflammatory gene transcription in differentiated immune cells under chronic microbial infections. However, the molecular mechanisms by which this transcriptional silencing process is regulated remain unclear. Here, we report that USP2, a deubiquitinase localized in the nucleus and induced by inflammatory signals, stabilizes SIX proteins through deubiquitination under inflammatory conditions. Consequently, the USP2-SIX complex acts in concert to control NF-κB-mediated inflammatory gene transcription by directly targeting gene promoters. Supporting this mechanism, Usp2-/- mice exhibit higher mortality during H1N1 infections, which phenocopies Six1-/- mice, attributed to elevated levels of life-threatening inflammatory mediators and exacerbated pathology. This study establishes a deubiquitinase-dependent transcriptional control of the inflammatory response to prevent immunopathology, offering new therapeutic avenues for combating infectious diseases.

Animals↗