ArticleOncogene2017
SKP2 loss destabilizes EZH2 by promoting TRAF6-mediated ubiquitination to suppress prostate cancer.
Article in Oncogene, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 42 papers.
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Who cites it
42 citing papers in PubMed, 55 citations in OpenAlex.
- Molecular Dynamics Simulation-Assisted siRNA Design for Dual-Ubiquitinated SKP2 Silencing via Ago2 Anchoring in Breast Cancer.ACS omega · 2026Article
- ZRANB1 depletion inhibits neuroblastoma progression by destabilizing MYCN through EZH2-mediated deubiquitination.Cell biology and toxicology · 2026Article
- Cyclophilin A stabilizes the capsid protein p72 to facilitate African swine fever virus replication.Nature communications · 2026Article
- TRIM26-mediated regulation of TRAF6 ubiquitination enhances host immune response during Toxoplasma gondii infection.Cellular and molecular life sciences : CMLS · 2026Article
- SKP2 in Cancer: From Molecular Regulation to Therapeutic Vulnerabilities and Translational Perspectives.Drug design, development and therapy · 2026Review
- Decitabine promotes degradation of DNMT1 and EZH2 via the ubiquitination pathway and inhibits colorectal cancer progression.Cellular oncology (Dordrecht, Netherlands) · 2025Article
- Novel Skp1 inhibitor has potent preclinical efficacy against castration-resistant prostate cancer.British journal of cancer · 2025Article
- The role of ubiquitination and deubiquitination in urological tumours.Frontiers in pharmacology · 2025Review
- Increased translation driven by non-canonical EZH2 creates a synthetic vulnerability in enzalutamide-resistant prostate cancer.Nature communications · 2024Article
- Enhancer of Zeste Homolog 2 Protects Mucosal Melanoma from Ferroptosis via the KLF14-SLC7A11 Signaling Pathway.Cancers · 2024Article
- SUMO E3 ligase MUL1 inhibits lymph node metastasis of bladder cancer by mediating mitochondrial HSPA9 translocation.International journal of biological sciences · 2024Article
- Tumor Necrosis Factor Receptor-Associated Factor 6 and Human Cancer: A Systematic Review of Mechanistic Insights, Functional Roles, and Therapeutic Potential.Journal of Cancer · 2024Review
- Effect of ubiquitin protease system on DNA damage response in prostate cancer (Review).Experimental and therapeutic medicine · 2024Review
- Multiomics characteristics and immunotherapeutic potential of EZH2 in pan-cancer.Bioscience reports · 2023Article
- EZH2: An Accomplice of Gastric Cancer.Cancers · 2023Review
- Role of K63-linked ubiquitination in cancer.Cell death discovery · 2022Review
- IGF2BP1 Promotes Proliferation of Neuroendocrine Neoplasms by Post-Transcriptional Enhancement of EZH2.Cancers · 2022Article
- MicroRNA-21 deficiency suppresses prostate cancer progression through downregulation of the IRS1-SREBP-1 signaling pathway.Cancer letters · 2022Article
- Palmitic Acid-Induced miR-429-3p Impairs Myoblast Differentiation by Downregulating CFL2.International journal of molecular sciences · 2021Article
- HFD-induced TRAF6 upregulation promotes liver cholesterol accumulation and fatty liver development via EZH2-mediated miR-429/PPARα axis.Molecular therapy. Nucleic acids · 2021Article
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
Abstract
EZH2 is crucial for the progression of prostate cancer (PCa) and castration-resistant prostate cancer (CRPC) through upregulation and activation of progenitor genes, as well as androgen receptor (AR)-target genes. However, the mechanisms by which EZH2 is regulated in PCa and CRPC remain elusive. Here we report that EZH2 is post-transcriptionally regulated by SKP2 in vitro in cultured cells and in vivo in mouse models. We observed aberrant upregulation of Skp2, Ezh2 and histone H3 lysine 27 trimethylation (H3K27me3) in both Pten null mouse embryonic fibroblasts (MEFs) and Pten null mouse prostate tissues. Loss of Skp2 resulted in a striking decrease of Ezh2 levels in Pten/Trp53 double-null MEFs and in prostate tumors of Pten/Trp53 double-null mutant mice. SKP2 knockdown decreased EZH2 levels in human PCa cells through upregulation of TRAF6-mediated and lysine(K) 63-linked ubiquitination of EZH2 for degradation. Ectopic expression of TRAF6 promoted the K63-linked ubiquitination of EZH2 to decrease EZH2 and H3K27me3 levels in PCa cells. In contrast, TRAF6 knockdown resulted in a reduced EZH2 ubiquitination with an increase of EZH2 and H3K27me3 levels in PCa cells. Furthermore, the catalytically dead mutant TRAF6 C70A abolished the TRAF6-mediated polyubiquitination of recombinant human EZH2 in vitro. Most importantly, a concurrent elevation of Skp2 and Ezh2 was found in CRPC tumors of Pten/Trp53 mutant mice, and expression levels of SKP2 and EZH2 were positively correlated in human PCa specimens. Taken together, our findings revealed a novel mechanism on EZH2 ubiquitination and an important signaling network of SKP2-TRAF6-EZH2/H3K27me3, and targeting SKP2-EZH2 pathway may be a promising therapeutic strategy for CRPC treatment.
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Registered trials
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.