Small cell lung cancer (SCLC) responds exceptionally well to cytotoxic chemotherapy. However, relapse with the emergence of chemoresistant disease is rapid and accompanied by poor treatment outcomes. To understand the genetic basis of chemoresistance in SCLC, we apply in vivo CRISPR deletion screening to patient-derived xenograft (PDX) models. Top screen hits include genes encoding components of the transcriptional co-activator SAGA (Spt-Ada-Gcn5 acetyltransferase) complex. We demonstrate that deletion of the SAGA deubiquitylase USP22 confers cisplatin-etoposide resistance in two chemosensitive PDX models, and that restoring expression in a PDX model harboring homozygous truncating mutation of USP22 re-sensitizes tumors to chemotherapy. USP22 loss increases gene body histone H2AK119 monoubiquitylation at key regulators of neuronal differentiation and suppresses neural and neuroendocrine gene expression including targets of ASCL1. Chemoresistance following USP22 loss reflects attenuated

Mutations in TP53, the gene for the tumour suppressor protein p53, are among the most common lesions in epithelial cancers, but how losing p53 drives the…

Deubiquitinase USP22 maintains B cell homeostasis through the CHD4-CD19 signaling axis and is dysregulated in Kawasaki disease

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid protein (SARS-CoV-2 NP) plays a pivotal role in viral infection by binding to viral RNA, stabilizing the viral genome, and pro...

We identified two genomic variants close to the RAB27A and USP22 genes that contribute to the risk of breast cancer in South African Black women...

Small cell lung cancer (SCLC) is one of the deadliest cancers with a five-year survival rate below 6 percent. It initially responds well to standard chemotherapy with cisplatin and etoposide, but nearly every patient relapses with drug-resistant disease within months. The genetic drivers of that resistance have remained largely unknown. A team led by David

Small cell lung cancer (SCLC) is one of the deadliest cancers with a five-year survival rate below 6 percent. It initially responds well to standard chemotherapy with cisplatin and etoposide, but nearly every patient relapses with drug-resistant disease within months. The genetic drivers of that resistance have remained largely unknown. A team led by David

Although the genetic basis of breast cancer has been explored, most studies have been on European populations. Here, the authors perform a genome-wide association study of breast cancer in Black South...

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nucleocapsid protein (SARS-CoV-2 NP) plays a pivotal role in viral infection by binding to viral RNA, stabilizing the viral genome, and pro...

Read the full paper: USP22 Inhibition Potentiates GPC3 Chimeric Antigen Receptor Macrophages Efficacy in Hepatocellular Carcinoma by Downregulating Tumor CD24 Expression

Read the full paper: Decoding the Oncogenic Role of USP22 Through Pan‐Cancer Genomic and Epigenetic Analysis

Immune checkpoint blockade (ICB), including PD-1/PD-L1 inhibitors, has transformed cancer therapy but benefits only a subset of patients. Understanding how PD-L1 is regulated and identifying strategies to overcome resistance remain critical. Here, we identify SIRT2 as a key positive regulator of PD-L1 across multiple human cancers. Unexpectedly, SIRT2 did not act at the transcriptional level but stabilized PD-L1 protein by preventing ubiquitin-mediated degradation. Mechanistically, SIRT2 maintained the protein stability of USP22, a PD-L1 deubiquitinase. Loss of SIRT2 reduced USP22 levels, whereas ectopic USP22 fully rescued PD-L1 expression and reversed the enhanced antitumor immunity induced by SIRT2 inhibition. We further show that SIRT2 directly deacetylates USP22 at K382 and K505 within its catalytic domain, promoting USP22 deubiquitinase activity and protecting both itself and its substrates from degradation. Our findings reveal a molecular mechanism by which an acetylation–deacetylation switch dynamically regulates deubiquitinase catalytic activity. Therapeutically, SIRT2 inhibition synergized with PD-1/PD-L1 blockade and USP22 inhibition to enhance antitumor immunity. Consistently, protein, but not mRNA, levels of SIRT2, USP22, and PD-L1 positively correlated in human bladder cancer and melanoma. Together, these findings define a SIRT2/USP22/PD-L1 axis driving tumor immune evasion and highlight SIRT2 as a promising target to improve ICB efficacy.

South African scientists have identified two new breast cancer genes -- RAB27A and USP22 -- in Black women, marking the first GWAS of its kind on the continent. This breakthrough highlights the need for Africa-centred genomic research and tools to improve cancer risk prediction and treatment.

South African scientists have identified two new breast cancer genes—RAB27A and USP22—in Black women, marking the first GWAS of its kind on the continent. This breakthrough highlights the need for Africa-centred genomic research and tools to improve cancer risk prediction and treatment.

Communications Biology - Ubiquitin-specific peptidase 22 (USP22) is identified as a key chromatin-based barrier to human iPSC derivation through a chromatin-focused CRISPR-Cas9 screen.

Deubiquitinases regulate key oncogenic and immune pathways but have proven challenging to exploit therapeutically. Among them, ubiquitin-specific protease 22 (USP22) has emerged as a molecule of interest due to its involvement in both tumor-intrinsic programs and tumor-immune interactions. In this review, we synthesize current evidence describing how USP22 modulates oncogenic transcriptional states and immune evasion. Tumor-intrinsically, USP22 has been implicated in stabilizing select oncogenic factors and shaping chromatin accessibility in ways that can reinforce proliferation, survival, stem-like properties, and metastatic potential. In parallel, USP22 influences antitumor immunity by modulating MHC-I-mediated antigen presentation, immune checkpoint expression, and the fitness of intratumoral regulatory T cells. We discuss emerging pharmacological approaches to target USP22, the limitations of current inhibitor strategies, and the importance of distinguishing direct enzymatic functions from indirect transcriptional consequences. Together, these insights suggest that USP22 inhibition may offer a therapeutic strategy with dual effects on tumor biology and antitumor immunity.

Deubiquitinases regulate key oncogenic and immune pathways but have proven challenging to exploit therapeutically. Among them, ubiquitin-specific protease 22 (USP22) has emerged as a molecule of interest due to its involvement in both tumor-intrinsic programs and tumor-immune interactions. In this review, we synthesize current evidence describing how USP22 modulates oncogenic transcriptional states and immune evasion. Tumor-intrinsically, USP22 has been implicated in stabilizing select oncogenic factors and shaping chromatin accessibility in ways that can reinforce proliferation, survival, stem-like properties, and metastatic potential. In parallel, USP22 influences antitumor immunity by modulating MHC-I-mediated antigen presentation, immune checkpoint expression, and the fitness of intratumoral regulatory T cells. We discuss emerging pharmacological approaches to target USP22, the limitations of current inhibitor strategies, and the importance of distinguishing direct enzymatic functions from indirect transcriptional consequences. Together, these insights suggest that USP22 inhibition may offer a therapeutic strategy with dual effects on tumor biology and antitumor immunity.

Neuropsychopharmacology - Knockdown of USP22 alleviates LPS-induced microglial inflammation and mouse depressive-like behaviors via KAT2A

Neuropsychopharmacology - Knockdown of USP22 alleviates LPS-induced microglial inflammation and mouse depressive-like behaviors via KAT2A

Cell Death & Differentiation - Akt-mediated RALY phosphorylation functions as a molecular switch governing c-Myc stability