ArticleCell death and differentiation2024
The PML1-WDR5 axis regulates H3K4me3 marks and promotes stemness of estrogen receptor-positive breast cancer.
Article in Cell death and differentiation, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers, 1 of them a synthesis that pooled it.
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15 citing papers in PubMed, 1 synthesis or guideline pooled it, 14 citations in OpenAlex.
- Multimodal deep learning for predicting neoadjuvant treatment outcomes in breast cancer: a systematic review.Biology direct · 2025Pooled it
- Decoding WDR5-Mediated Interactions in Gliomas: Implications for Targeted Therapy.Medicinal research reviews · 2026Review
- TRIM Protein Superfamily in Breast Cancer: Yin and Yang.Biochemical genetics · 2026Review
- IFI30 reprograms glioblastoma-associated macrophage and induces immune evasion by MAFF/PTGS2 pathway.Acta pharmaceutica Sinica. B · 2026Article
- A PML1-CCL5-PI3K/MAPK feedback loop governs survival of endocrine-resistant breast cancer cells.Cell death and differentiation · 2026Review
- Identification and Prognostic Analysis of Immune-Related Genes Co-Regulated by Key Histone Modifications in Breast Cancer.Current issues in molecular biology · 2026Article
- GLYATL1 is associated with metabolic and epigenetic changes and with endocrine resistance in luminal breast cancer.Clinical epigenetics · 2026Article
- PXL: a Nucleic Acid-Binding Module of Promyelocytic Leukemia Protein.bioRxiv : the preprint server for biology · 2026Article
- Alternative Splicing: Molecular Mechanisms, Biological Functions, Diseases, and Potential Therapeutic Targets.MedComm · 2025Review
- ADNP is essential for sex-dependent hippocampal neurogenesis, through male unfolded protein response and female mitochondrial gene regulation.Molecular psychiatry · 2025Article
- Epigenetic regulatory protein chromobox family regulates multiple signalling pathways and mechanisms in cancer.Clinical epigenetics · 2025Review
- Cross-trait multivariate GWAS confirms health implications of pubertal timing.Nature communications · 2025Article
- Cancer stem cell specificity as new targets in breast tumor treatment.Oncology research · 2025Review
- Transglutaminase 2-mediated histone monoaminylation and its role in cancer.Bioscience reports · 2024Review
- Expanded profiling of WD repeat domain 5 inhibitors reveals actionable strategies for the treatment of hematologic malignancies.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
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10 authors at 3 institutions in 1 country.
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Abstract
The alternative splicing of PML precursor mRNA gives rise to various PML isoforms, yet their expression profile in breast cancer cells remains uncharted. We discovered that PML1 is the most abundant isoform in all breast cancer subtypes, and its expression is associated with unfavorable prognosis in estrogen receptor-positive (ER+) breast cancers. PML depletion reduces cell proliferation, invasion, and stemness, while heterologous PML1 expression augments these processes and fuels tumor growth and resistance to fulvestrant, an FDA-approved drug for ER+ breast cancer, in a mouse model. Moreover, PML1, rather than the well-known tumor suppressor isoform PML4, rescues the proliferation of PML knockdown cells. ChIP-seq analysis reveals significant overlap between PML-, ER-, and Myc-bound promoters, suggesting their coordinated regulation of target gene expression, including genes involved in breast cancer stem cells (BCSCs), such as JAG1, KLF4, YAP1, SNAI1, and MYC. Loss of PML reduces BCSC-related gene expression, and exogenous PML1 expression elevates their expression. Consistently, PML1 restores the association of PML with these promoters in PML-depleted cells. We identified a novel association between PML1 and WDR5, a key component of H3K4 methyltransferase (HMTs) complexes that catalyze H3K4me1 and H3K4me3. ChIP-seq analyses showed that the loss of PML1 reduces H3K4me3 in numerous loci, including BCSC-associated gene promoters. Additionally, PML1, not PML4, re-establishes the H3K4me3 mark on these promoters in PML-depleted cells. Significantly, PML1 is essential for recruiting WDR5, MLL1, and MLL2 to these gene promoters. Inactivating WDR5 by knockdown or inhibitors phenocopies the effects of PML1 loss, reducing BCSC-related gene expression and tumorsphere formation and enhancing fulvestrant's anticancer activity. Our findings challenge the conventional understanding of PML as a tumor suppressor, redefine its role as a promoter of tumor growth in breast cancer, and offer new insights into the unique roles of PML isoforms in breast cancer.
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