ArticleOncogene2020
Cancer-derived UTX TPR mutations G137V and D336G impair interaction with MLL3/4 complexes and affect UTX subcellular localization.
Article in Oncogene, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 46 citations in OpenAlex.
- Enhancer and metabolic rewiring by KMT2C-COMPASS or KMT2D-COMPASS family loss in cancer creates druggable vulnerabilities.Nature reviews. Cancer · 2026Review
- Histone lysine demethylases in breast cancer: molecular mechanisms, biological functions, and therapeutic intervention.Molecular cancer · 2025Review
- Histone Demethylase UTX Suppresses Tumor Cell Proliferation by Regulating Stress Granules.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Inhibition of WAC alleviates the chondrocyte proinflammatory secretory phenotype and cartilage degradationActa pharmaceutica Sinica. B · 2025Article
- KDM6A Deficiency Induces Myeloid Bias and Promotes CMML-Like Disease Through JAK/STAT3 Activation by Repressing SOCS3.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Review
- Article
- KDM6A-SND1 interaction maintains genomic stability by protecting the nascent DNA and contributes to cancer chemoresistance.Nucleic acids research · 2024Article
- Inactivation of KDM6A promotes the progression of colorectal cancer by enhancing the glycolysis.European journal of medical research · 2024Article
- The emerging roles of histone demethylases in cancers.Cancer metastasis reviews · 2024Review
- Catalytic domain-dependent and -independent transcriptional activities of the tumour suppressor histone H3K27 demethylase UTX/KDM6A in specific cancer types.Epigenetics · 2023Article
- Structural and functional complexity of HSP90 in cellular homeostasis and disease.Nature reviews. Molecular cell biology · 2023Review
- Alternative mRNA Splicing Controls the Functions of the Histone H3K27 Demethylase UTX/KDM6A.Cancers · 2023Article
- Combined Kdm6a and Trp53 Deficiency Drives the Development of Squamous Cell Skin Cancer in Mice.The Journal of investigative dermatology · 2023Article
- Implications of disease-related mutations at protein-protein interfaces.Current opinion in structural biology · 2022Review
- PTIP-Associated Protein 1: More Than a Component of the MLL3/4 Complex.Frontiers in genetics · 2022Review
- Decreased Jumonji Domain-Containing 3 at the Promoter Downregulates Hematopoietic Progenitor Kinase 1 Expression and Cytoactivity of T Follicular Helper Cells from Systemic Lupus Erythematosus Patients.Journal of immunology research · 2022Article
- KDM6A mutations promote acute cytoplasmic DNA release, DNA damage response and mitosis defects.BMC molecular and cell biology · 2021Article
- A KDM6 inhibitor potently induces ATF4 and its target gene expression through HRI activation and by UTX inhibition.Scientific reports · 2021Article
- Article
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Authors and funding
8 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The ubiquitously transcribed tetratricopeptide repeat on X chromosome (UTX) is a major histone H3 lysine 27 (H3K27) demethylase and the mixed-lineage leukemia (MLL) proteins are the H3K4 methyltransferases. UTX is one of the major components of MLL3- and MLL4-containing (MlLL3/4) complexes and likely has functions within the complexes. Although UTX is frequently mutated in various types of cancer and is thought to play a crucial role as a tumor suppressor, the importance of UTX interaction with MLL3/4 complexes in cancer formation is poorly understood. Here, we analyzed the ability of cancer-derived UTX mutant proteins to interact with ASH2L, which is a common core component of all the MLL complexes, and MLL3/4-specific components PTIP and PA1, and found that several single-amino acid substitution mutations in the tetratricopeptide repeat (TPR) affect UTX interaction with these components. Interaction-compromised mutants G137V and D336G and a TPR-deleted mutant Δ80-397 were preferentially localized to the cytoplasm, suggesting that UTX is retained in the nucleus by MLL3/4 complexes through their interaction with the TPR. Intriguingly, WT UTX suppressed colony formation in soft agar, whereas G137V failed. This suggests that interaction of UTX with MLL3/4 complex plays a crucial role in their tumor suppressor function. Preferential cytoplasmic localization was also observed for endogenous proteins of G137V and another mutant G137VΔ138 in HCT116 created by CRISPR-Cas9 gene editing. Interestingly, expression levels of these mutants were low and MG312 stabilized both endogenous as well as exogenous G137V proteins. These results reveal a novel mechanism of UTX regulation and reinforce the importance of UTX interaction with MLL3/4 complexes in cancer formation.
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