Yongxin Zou

PR domain zinc finger protein 1 (PRDM1) functions as a critical transcriptional repressor. The role of PRDM1 in various tumors is controversial, and its specific mechanism in bladder cancer (BCa) remains unclear. In the present study, we demonstrated that PRDM1 expression is downregulated in both human BCa tissues and BBN-induced mouse models of BCa. Gain- and loss-of-function experiments revealed that PRDM1 delays cell cycle progression, suppresses BCa cell proliferation, and enhances chemosensitivity, whereas PRDM1 knockdown promotes cell proliferation and induces chemoresistance. Ovarian tumor deubiquitinase 6 A (OTUD6A) is a deubiquitinating enzyme that prevents the proteasomal degradation of CDC6. PRDM1 directly binds to the OTUD6A promoter and suppresses its transcription, thereby reducing CDC6 deubiquitination and promoting its degradation. Knockdown of CDC6 or OTUD6A abrogates the protective effects of PRDM1 both in vitro and in vivo. Consistently, PRDM1 expression is negatively correlated with CDC6 and OTUD6A expression in BCa tissues. Collectively, these findings demonstrate that PRDM1 acts as a tumor suppressor in BCa by inhibiting OTUD6A transcription and promoting CDC6 degradation. We propose a PRDM1‒OTUD6A‒CDC6 axis model, providing novel insights into PRDM1 as a potential therapeutic target in BCa.

Wogonin is a compound extracted from the medicinal plant Scutellaria baicalensis Geogi and has been found to exert antitumor activities in a variety of malignancies. However, the molecular mechanisms involved in the anti-gastric cancer (GC) effects of wogonin remain poorly understood. In the present study, we found that wogonin treatment inhibited the proliferation of GC cells, induced apoptosis and G0/G1 cell arrest, and suppressed the migration and invasion of SGC-7901 and BGC-823 cells in vitro. In addition, wogonin inhibited in vivo tumor growth in SGC-7901 xenograft mice. Transcriptomic analysis suggested that wogonin affected several signaling pathways closely related to tumor proliferation and metastasis, including the STAT3 signaling pathway. Further research indicated that wogonin may exert antitumor effects in GC cells by downregulating the JAK-STAT3 pathway. Altogether, our results demonstrate that wogonin exerts antitumor effects by perturbing JAK-STAT3 signaling in GC cells and that wogonin may be a potential therapeutic option for GC.

Acute kidney injury (AKI) caused by nephrotoxins, ischemia reperfusion (IR) or sepsis is associated with high morbidity and mortality. Unveiling new mechanisms underlying AKI can help develop new therapeutic strategy. Cullin 4B (CUL4B) is a scaffold protein in the CUL4B-RING E3 ubiquitin ligase (CRL4B) complex. Here, we demonstrate that CUL4B can protect kidneys from acute injury induced by cisplatin and IR. CUL4B is upregulated in mouse tubular epithelial cells (TECs) after cisplatin treatment or IR. Loss of CUL4B in kidneys exacerbates renal injury, inflammation, and apoptosis of TECs caused by cisplatin and IR. Transcriptome analysis reveals that Cul4b deficiency enhances injury-induced PAI-1 expression. CUL4B suppresses PAI-1 expression by promoting polyubiquitination and degradation of p53. Inhibition of either PAI-1 or p53 can prevent the aggravated renal injury and inflammation caused by loss of CUL4B. Our work has identified the kidney-protective role of CUL4B against acute injury.

Mesenchymal stem cells (MSCs) are multipotent stem cells that can exert immunomodulatory capacity upon stimulation with pro-inflammatory cytokines. Our previous work has identified Cullin 4B (CUL4B), a scaffold protein in the CUL4B-RING E3 ligase (CRL4B) complex, as a key regulator in the differentiation of MSCs. Here, we demonstrate the critical role of CUL4B in regulating the immunosuppressive function of MSCs. When stimulated with pro-inflammatory cytokines, MSCs lacking CUL4B display enhanced immunosuppressive capacity, which is mediated by the elevated inducible nitric oxide synthase (iNOS). TGF-β signaling can suppress iNOS by inhibiting its transcription as well as promoting its protein degradation. We show that the CRL4B complex cooperates with PRC2 complex and HDACs to repress transcription of Dlx1 and Pmepa1, two inhibitors of TGF-β signaling, leading to decreased expression and accelerated degradation of iNOS. Our study unveils the CRL4B complex as a potential therapeutic target in promoting the immunosuppressive capacity of MSCs.

Background: CDC6 is an oncogenic protein whose expression level fluctuates during the cell cycle. Although several E3 ubiquitin ligases responsible for the ubiquitin-mediated proteolysis of CDC6 have been identified, the deubiquitination pathway for CDC6 has not been investigated. Methods: The proteome-wide deubiquitinase (DUB) screening was used to identify the potential regulator of CDC6. Immunofluorescence, protein half-life and deubiquitination assays were performed to determine the protein stability of CDC6. Gain- and loss-of-function experiments were implemented to analyse the impacts of OUTD6A-CDC6 axis on tumour growth and chemosensitivity in vitro. N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN)-induced conditional Otud6a knockout (CKO) mouse model and tumour xenograft model were performed to analyse the role of OTUD6A-CDC6 axis in vivo. Tissue specimens were used to determine the association between OTUD6A and CDC6. Results: OTUD6A interacts with, depolyubiquitinates and stabilizes CDC6 by removing K6-, K33-, and K48-linked polyubiquitination. Moreover, OTUD6A promotes cell proliferation and decreases sensitivity to chemotherapy by upregulating CDC6. CKO mice are less prone to BCa tumorigenesis induced by BBN, and knockdown of OTUD6A inhibits tumour progression in vivo. Furthermore, OTUD6A protein level has a positive correlation with CDC6 protein level, and high protein levels of OTUD6A and CDC6 are associated with poor prognosis in patients with bladder cancer. Conclusions: We reveal an important yet missing piece of novel DUB governing CDC6 stability. In addition, our findings propose a model for the OTUD6A-CDC6 axis that provides novel insights into cell cycle and chemosensitivity regulation, which may become a potential biomarker and promising drug target for cancer treatment.

Mutation in CUL4B gene is one of the most common causes for X-linked intellectual disability (XLID). CUL4B is the scaffold protein in CUL4B-RING ubiquitin ligase (CRL4B) complex. While the roles of CUL4B in cancer progression and some developmental processes like adipogenesis, osteogenesis, and spermatogenesis have been studied, the mechanisms underlying the neurological disorders in patients with CUL4B mutations are poorly understood. Here, using 2D neuronal culture and cerebral organoids generated from the patient-derived induced pluripotent stem cells and their isogenic controls, we demonstrate that CUL4B is required to prevent premature cell cycle exit and precocious neuronal differentiation of neural progenitor cells. Moreover, loss-of-function mutations of CUL4B lead to increased synapse formation and enhanced neuronal excitability. Mechanistically, CRL4B complex represses transcription of PPP2R2B and PPP2R2C genes, which encode two isoforms of the regulatory subunit of protein phosphatase 2 A (PP2A) complex, through catalyzing monoubiquitination of H2AK119 in their promoter regions. CUL4B mutations result in upregulated PP2A activity, which causes inhibition of AKT and ERK, leading to premature cell cycle exit. Activation of AKT and ERK or inhibition of PP2A activity in CUL4B mutant organoids rescues the neurogenesis defect. Our work unveils an essential role of CUL4B in human cortical development.

Dysregulation of MOF (also known as MYST1, KAT8), a highly conserved H4K16 acetyltransferase, plays important roles in human cancers. However, its expression and function in esophageal squamous cell carcinoma (ESCC) remain unknown. Here, we report that MOF is highly expressed in ESCC tumors and predicts a worse prognosis. Depletion of MOF in ESCC significantly impedes tumor growth and metastasis both in vitro and in vivo, whereas ectopic expression of MOF but not catalytically inactive mutant (MOF-E350Q) promotes ESCC progression, suggesting that MOF acetyltransferase activity is crucial for its oncogenic activity. Further analysis reveals that USP10, a deubiquitinase highly expressed in ESCC, binds to and deubiquitinates MOF at lysine 410, which protects it from proteosome-dependent protein degradation. MOF stabilization by USP10 promotes H4K16ac enrichment in the ANXA2 promoter to stimulate ANXA2 transcription in a JUN-dependent manner, which subsequently activates Wnt/β-Catenin signaling to facilitate ESCC progression. Our findings highlight a novel USP10/MOF/ANXA2 axis as a promising therapeutic target for ESCC.

Lung cancer is the leading cause of cancer-related death worldwide. KRAS mutations are the most common oncogenic alterations found in lung cancer. Unfortunately, treating KRAS-mutant lung adenocarcinoma (ADC) remains a major oncotherapeutic challenge. Here, we used both autochthonous and transplantable KRAS-mutant tumor models to investigate the role of tumor-derived CUL4B in KRAS-driven lung cancers. We showed that knockout or knockdown of CUL4B promotes lung ADC growth and progression in both models. Mechanistically, CUL4B directly binds to the promoter of Cxcl2 and epigenetically represses its transcription. CUL4B deletion increases the expression of CXCL2, which binds to CXCR2 on myeloid-derived suppressor cells (MDSCs) and promotes their migration to the tumor microenvironment. Targeting of MDSCs significantly delayed the growth of CUL4B knockdown KRAS-mutant tumors. Collectively, our study provides mechanistic insights into the novel tumor suppressor-like functions of CUL4B in regulating KRAS-driven lung tumor development.

Chemotherapy is a common strategy to treat cancer. However, acquired resistance and metastasis are the major obstacles to successful treatment. Anastasis is a process by which cells survive executioner caspase activation when facing apoptotic stress. Here we demonstrate that colorectal cancer cells can undergo anastasis after transient exposure to chemotherapeutic drugs. Using a lineage tracing system to label and isolate cells that have experienced executioner caspase activation in response to drug treatment, we show that anastasis grants colorectal cancer cells enhanced migration, metastasis, and chemoresistance. Mechanistically, treatment with chemotherapeutic drugs induces upregulated expression of cIAP2 and activation of NFκB, which are required for cells to survive executioner caspase activation. The elevated cIAP2/NFκB signaling persists in anastatic cancer cells to promote migration and chemoresistance. Our study unveils that cIAP2/NFκB-dependent anastasis promotes acquired resistance and metastasis after chemotherapy.