ArticleOncogene2023
UHRF1/UBE2L6/UBR4-mediated ubiquitination regulates EZH2 abundance and thereby melanocytic differentiation phenotypes in melanoma.
Article in Oncogene, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 17 citations in OpenAlex.
- ZRANB1-mediated EZH2 stabilization drives S100B/S100A4 transcriptional activation and corneal neovascularization in alkali burns.Biology direct · 2026Article
- Structure-function relationship of alpha-synuclein fibrillar polymorphs derived from distinct synucleinopathies.Molecular systems biology · 2026Article
- EZH2 in Acral Lentiginous Melanoma: Molecular, Epigenetic, and Therapeutic Perspectives.Oncology research · 2026Review
- Decitabine promotes degradation of DNMT1 and EZH2 via the ubiquitination pathway and inhibits colorectal cancer progression.Cellular oncology (Dordrecht, Netherlands) · 2025Article
- Ubiquitin-conjugating enzyme E2S serves as a prognostic marker for skin cutaneous melanoma.Translational cancer research · 2025Article
- Discovery and Characterization of Uracil Derivatives Targeting the Set-and-Ring Domain of UHRF1.Journal of chemical information and modeling · 2025Article
- Impact of Tyrosine Kinase Inhibitors on the Expression Pattern of Epigenetic Regulators.Cancers · 2025Article
- Prognostic model of ubiquitination-related genes in ovarian cancer based on transcriptomic analysis and experimental validation.Frontiers in immunology · 2025Article
- SIRT6 deficiency impairs the deacetylation and ubiquitination of UHRF1 to strengthen glycolysis and lactate secretion in bladder cancer.Cell & bioscience · 2024Article
- Histone lysine methylation modifiers controlled by protein stability.Experimental & molecular medicine · 2024Review
- Histone lysine methylation modifiers controlled by protein stability.Experimental & molecular medicine · 2024Review
- Hypoxia makes EZH2 inhibitor not easy-advances of crosstalk between HIF and EZH2.Life metabolism · 2024Article
- lncRNAs-EZH2 interaction as promising therapeutic target in cutaneous melanoma.Frontiers in molecular biosciences · 2023Review
Corrections and comments
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Authors and funding
15 authors at 4 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Cellular heterogeneity in cancer is linked to disease progression and therapy response, although mechanisms regulating distinct cellular states within tumors are not well understood. We identified melanin pigment content as a major source of cellular heterogeneity in melanoma and compared RNAseq data from high-pigmented (HPCs) and low-pigmented melanoma cells (LPCs), suggesting EZH2 as a master regulator of these states. EZH2 protein was found to be upregulated in LPCs and inversely correlated with melanin deposition in pigmented patient melanomas. Surprisingly, conventional EZH2 methyltransferase inhibitors, GSK126 and EPZ6438, had no effect on LPC survival, clonogenicity and pigmentation, despite fully inhibiting methyltransferase activity. In contrast, EZH2 silencing by siRNA or degradation by DZNep or MS1943 inhibited growth of LPCs and induced HPCs. As the proteasomal inhibitor MG132 induced EZH2 protein in HPCs, we evaluated ubiquitin pathway proteins in HPC vs LPCs. Biochemical assays and animal studies demonstrated that in LPCs, the E2-conjugating enzyme UBE2L6 depletes EZH2 protein in cooperation with UBR4, an E3 ligase, via ubiquitination at EZH2's K381 residue, and is downregulated in LPCs by UHRF1-mediated CpG methylation. Targeting UHRF1/UBE2L6/UBR4-mediated regulation of EZH2 offers potential for modulating the activity of this oncoprotein in contexts in which conventional EZH2 methyltransferase inhibitors are ineffective.
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