ArticleNature medicine2018
Resetting the epigenetic balance of Polycomb and COMPASS function at enhancers for cancer therapy.
Article in Nature medicine, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 123 papers.
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Who cites it
123 citing papers in PubMed, 193 citations in OpenAlex.
- BAP1 and UTX are dispensable for transcription-driven Polycomb erasure but essential for enhancer establishment.The Journal of biological chemistry · 2026Article
- MLL3 and MLL4 sustain hematopoietic stem cell multipotency by opposing a B-cell default state.Blood · 2026Article
- KMT2D loss drives adeno-to-squamous transition and sensitizes TKI-resistant lung cancer to AURKA inhibition.Cell death and differentiation · 2026Article
- Mapping of the hSOX10 Proximal Protein Interactome in Human Melanoma.Journal of proteome research · 2026Article
- Enhancer and metabolic rewiring by KMT2C-COMPASS or KMT2D-COMPASS family loss in cancer creates druggable vulnerabilities.Nature reviews. Cancer · 2026Review
- KMT2C Loss Promotes NF2-Wildtype Meningioma Progression and Ferroptosis Sensitivity via Epigenetic Repression of Hippo Signaling.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Protease-mediated PRC1 dissociation promotes H2AK119ub remodeling during stress responses.The EMBO journal · 2026Article
- Polycomb repressive-deubiquitinase complex safeguards oocyte epigenome and female fertility by restraining Polycomb activity.Nature communications · 2026Article
- A tryptophan-phenylalanine binding motif for the histone methyltransferases MLL4 and MLL3.The Journal of biological chemistry · 2026Article
- Genome-wide screenings identify BAP1 as a synthetic-lethality target with CDK4/6 inhibitors.Science advances · 2026Article
- Gallbladder mucinous carcinoma in a child with metachromatic leukodystrophy, case report and literature review.BMC pediatrics · 2026Review
- Tumor suppressor BAP1 emerges as a key regulator of metabolism and cell death in tumors.Frontiers in cell and developmental biology · 2026Review
- Molecular mechanisms of KMT2C alterations in gastrointestinal cancers: enhancer network destabilization, lineage plasticity, and clinical translation.Frontiers in immunology · 2026Review
- LncRNA-Histone Modification Crosstalk: Orchestrating Cancer Pathobiology.Naunyn-Schmiedeberg's archives of pharmacology · 2025Review
- Novel modifiers of oncoprotein-mediated Polycomb inhibition in Drosophila melanogaster.Genetics · 2025Article
- KDM6A phosphorylation suppresses PER2 to confer a glycolytic vulnerability in HNSCC.Cell death & disease · 2025Article
- Article
- Proteomic Identification of IL4I1 as a Therapeutic Target in P53-Mutant Endometrial Cancer.Cancers · 2025Article
- Mapping of the hSOX10 protein interactome in human melanoma.bioRxiv : the preprint server for biology · 2025Article
- Article
63 more citing papers are in PubMed but not listed here.
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Authors and funding
19 authors at 1 institution in 1 country.
Funding
Abstract
The lysine methyltransferase KMT2C (also known as MLL3), a subunit of the COMPASS complex, implements monomethylation of Lys4 on histone H3 (H3K4) at gene enhancers. KMT2C (hereafter referred to as MLL3) frequently incurs point mutations across a range of human tumor types, but precisely how these lesions alter MLL3 function and contribute to oncogenesis is unclear. Here we report a cancer mutational hotspot in MLL3 within the region encoding its plant homeodomain (PHD) repeats and demonstrate that this domain mediates association of MLL3 with the histone H2A deubiquitinase and tumor suppressor BAP1. Cancer-associated mutations in the sequence encoding the MLL3 PHD repeats disrupt the interaction between MLL3 and BAP1 and correlate with poor patient survival. Cancer cells that had PHD-associated MLL3 mutations or lacked BAP1 showed reduced recruitment of MLL3 and the H3K27 demethylase KDM6A (also known as UTX) to gene enhancers. As a result, inhibition of the H3K27 methyltransferase activity of the Polycomb repressive complex 2 (PRC2) in tumor cells harboring BAP1 or MLL3 mutations restored normal gene expression patterns and impaired cell proliferation in vivo. This study provides mechanistic insight into the oncogenic effects of PHD-associated mutations in MLL3 and suggests that restoration of a balanced state of Polycomb-COMPASS activity may have therapeutic efficacy in tumors that bear mutations in the genes encoding these epigenetic factors.
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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.