Histone Demethylase UTX Suppresses Tumor Cell Proliferation by Regulating Stress Granules
UTX (also known as KDM6A) is a histone H3K27 demethylase that acts as an important tumor regulator. UTX has been reported to participate in genome-wide histone modifications and gene expression in tumorigenesis and its mutations are identified in human cancers. Here, UTX is demonstrated to localize both in the cytoplasm and nucleus, notably, cytoplasmic UTX forms puncta and co-localizes in stress granules (SGs) upon different stresses in vitro. Mechanistically, the TPR domain of UTX plays a critical role in regulating SG disassembly by interacting with G3BP1, the central hub of SG, to disrupt the scaffold network of SG under endoplasmic reticulum stress. Importantly, a clinical UTX mutation, D336G in TPR domain, increases cytoplasmic location of UTX, and stabilizes SG. While UTX<sup>D336G</sup> promotes, WT UTX or UTX<sup>TPR</sup> inhibits, cell growth and tumorigenesis by regulating SGs both in vitro and in nude mice, and such regulation is G3BP1 dependent. Together, the results suggest a novel cytoplasmic function of UTX as a negative regulator of SG homeostasis, which is involved in stress and disease states such as tumorigenesis.
Authors
- Kun Huang (ORCID: https://orcid.org/0000-0002-0808-2325)
- Yangkai Li (ORCID: https://orcid.org/0000-0001-5342-5078)
- Yushuo Xiao
- Tianyi Shi (ORCID: https://orcid.org/0000-0002-9204-9949)
- Xikai Liu (ORCID: https://orcid.org/0000-0002-9964-1873)
- Mei Xue (ORCID: https://orcid.org/0000-0001-5130-8855)
- Hua Su (ORCID: https://orcid.org/0000-0002-7245-2749)
- Yihao Zhou (ORCID: https://orcid.org/0000-0002-3779-9907)
- Linwei Yu (ORCID: https://orcid.org/0000-0002-0287-4970)
- Yong Liu (ORCID: https://orcid.org/0000-0001-7771-4181)
- Hong Chen (ORCID: https://orcid.org/0000-0003-3478-6139)
- Jiao Wang (ORCID: https://orcid.org/0000-0001-9875-5425)
- Yuchen Chen (ORCID: https://orcid.org/0000-0001-8558-3062)
- Xin-Ran Liu (ORCID: https://orcid.org/0009-0007-9591-5500)
- Ling Zheng (ORCID: https://orcid.org/0000-0002-7918-6682)
- Di Wu (ORCID: https://orcid.org/0000-0002-9001-139X)
- Yan Yuan
- Rong Qiu (ORCID: https://orcid.org/0009-0003-7516-7876)
Institutions
- Union Hospital (HK)
- Wuhan University (CN)
- Wuhan No.1 Hospital (CN)
- Tongji Hospital (CN)
- Huazhong University of Science and Technology (CN)
- Hubei University (CN)
Publication Details
- Journal
- Advanced Science
- Published
- 2025-06-19
- DOI
- https://doi.org/10.1002/advs.202501990
- Citations
- 3
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 2.42
Funders
- National Natural Science Foundation of China
- Natural Science Foundation of Hubei Province
- Wuhan University
- National Key Research and Development Program of China
- Fundamental Research Funds for the Central Universities