ArticleThe Journal of clinical investigation2017
Ubiquitination of tumor suppressor PML regulates prometastatic and immunosuppressive tumor microenvironment.
Article in The Journal of clinical investigation, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 51 papers.
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Who cites it
51 citing papers in PubMed, 86 citations in OpenAlex.
- Multicenter phase II trial of Camrelizumab combined with Apatinib and Eribulin in heavily pretreated patients with advanced triple-negative breast cancer.Nature communications · 2022Trial
- The promyelocytic leukemia PML protein coordinates immune evasion in triple-negative breast cancer via independent and converging mechanisms.Cell death and differentiation · 2026Article
- Wdr4 regulates ribosome biogenesis and intestinal homeostasis via let-7.EMBO reports · 2026Article
- A Perspective on Therapeutic Targeting Against Ubiquitin Ligases to Stabilize Tumor Suppressor Proteins.Cancers · 2025Review
- RNA modifications in cancer.MedComm · 2025Review
- Tumorigenesis Caused by Aberrant Expression of GANP, a Central Component in the Mammalian TREX-2 Complex-Lessons from Transcription-Coupled DNA Damages.International journal of molecular sciences · 2024Review
- A Multi-Omics Prognostic Model Capturing Tumor Stemness and the Immune Microenvironment in Clear Cell Renal Cell Carcinoma.Biomedicines · 2024Article
- Cilia defects upon loss of WDR4 are linked to proteasomal hyperactivity and ubiquitin shortage.Cell death & disease · 2024Article
- Ubiquitin modification in the regulation of tumor immunotherapy resistance mechanisms and potential therapeutic targets.Experimental hematology & oncology · 2024Review
- Phase separation of PML/RARα and BRD4 coassembled microspeckles governs transcriptional dysregulation in acute promyelocytic leukemia.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Multiple roles of arsenic compounds in phase separation and membraneless organelles formation determine their therapeutic efficacy in tumors.Journal of pharmaceutical analysis · 2024Review
- PML restrains p53 activity and cellular senescence in clear cell renal cell carcinoma.EMBO molecular medicine · 2024Article
- A novel m7G-related miRNA prognostic signature for predicting clinical outcome and immune microenvironment in colon cancer.Journal of Cancer · 2024Article
- M7G-related tumor immunity: novel insights of RNA modification and potential therapeutic targets.International journal of biological sciences · 2024Review
- Selection of M7G-related lncRNAs in kidney renal clear cell carcinoma and their putative diagnostic and prognostic role.BMC urology · 2023Article
- PTPN23 ubiquitination by WDR4 suppresses EGFR and c-MET degradation to define a lung cancer therapeutic target.Cell death & disease · 2023Article
- WDR4 promotes the progression and lymphatic metastasis of bladder cancer via transcriptional down-regulation of ARRB2.Oncogenesis · 2023Article
- Cancer Stem Cells and the Tumor Microenvironment in Tumor Drug Resistance.Stem cell reviews and reports · 2023Review
- Biological roles of RNA m7G modification and its implications in cancer.Biology direct · 2023Review
- NIR-II-absorbing diimmonium polymer agent achieves excellent photothermal therapy with induction of tumor immunogenic cell death.Journal of nanobiotechnology · 2023Article
Corrections and comments
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Authors and funding
17 authors at 8 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The tumor microenvironment plays an important role in tumor growth and metastasis. However, the mechanism by which tumor cells regulate the cell and non-cell constituents of surrounding stroma remains incompletely understood. Promyelocytic leukemia (PML) is a pleiotropic tumor suppressor, but its role in tumor microenvironment regulation is poorly characterized. PML is frequently downregulated in many cancer types, including lung cancer. Here, we identify a PML ubiquitination pathway that is mediated by WD repeat 4-containing cullin-RING ubiquitin ligase 4 (CRL4WDR4). Clinically, this PML degradation pathway is hyperactivated in lung cancer and correlates with poor prognosis. The WDR4/PML axis induces a set of cell-surface or secreted factors, including CD73, urokinase-type plasminogen activator receptor (uPAR), and serum amyloid A2 (SAA2), which elicit paracrine effects to stimulate migration, invasion, and metastasis in multiple lung cancer models. In xenograft and genetically engineered mouse models, the WDR4/PML axis elevates intratumoral Tregs and M2-like macrophages and reduces CD8+ T cells to promote lung tumor growth. These immunosuppressive effects were all reversed by CD73 blockade. Our study identifies WDR4 as an oncoprotein that negatively regulates PML via ubiquitination to promote lung cancer progression by fostering an immunosuppressive and prometastatic tumor microenvironment, suggesting the potential of immune-modulatory approaches for treating lung cancer with aberrant PML degradation.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.