Hypoxia-induced PRMT1 methylates HIF2β to promote breast tumorigenesis via enhancing glycolytic gene transcription
Hypoxia-induced metabolic reprogramming is closely linked to breast cancer progression. Through transcriptomic analysis, we identified PRMT1 as a direct target of hypoxia-inducible factor 1α (HIF1α) under hypoxic conditions in breast cancer cells. In turn, PRMT1 enhances the expression of HIF1α-driven glycolytic genes. Mechanistically, PRMT1 methylates HIF2β at arginine 42, facilitating the formation, chromatin binding, and the transcriptional activity of the HIF1α/HIF2β heterodimer. Genetic and pharmacological inhibition of PRMT1 suppresses HIF2β methylation, HIF1α/HIF2β heterodimer formation, chromatin binding, glycolytic gene expression, lactate production, and the malignant behaviors of breast cancer cells. Moreover, combination treatment with iPRMT1, a PRMT1 inhibitor, and menadione, an HIF1α/P300 interaction inhibitor, demonstrates synergistic effects in suppressing breast tumor growth. Clinically, PRMT1 and PRMT1-mediated HIF2β methylation were significantly elevated in breast tumors compared with adjacent normal tissues. In conclusion, our findings reveal the critical role of PRMT1-mediated arginine methylation in glycolytic gene expression, metabolic reprogramming, and breast tumor growth.
Authors
- Yan-Chao Chen
- Xianming Deng (ORCID: https://orcid.org/0000-0002-9354-5864)
- Guo-Sheng Hu (ORCID: https://orcid.org/0000-0002-7784-9171)
- Yan Zhao (ORCID: https://orcid.org/0000-0001-8088-4288)
- Fangmeng Fu (ORCID: https://orcid.org/0000-0002-3065-5708)
- Yaohui He (ORCID: https://orcid.org/0000-0002-8235-8924)
- Wen Liu (ORCID: https://orcid.org/0000-0003-3434-4162)
- Yiran Wang
- Wenjuan Li (ORCID: https://orcid.org/0000-0002-2231-7338)
- Cheng Yan (ORCID: https://orcid.org/0000-0002-5021-6841)
- Jingjing Yang (ORCID: https://orcid.org/0000-0002-4191-4138)
- Meiyan Li (ORCID: https://orcid.org/0009-0008-1708-0621)
- Yian Lin (ORCID: https://orcid.org/0000-0002-6343-7942)
- Weiling He
- Yi-qin Zou
- Yuhua Tan
- Xinyu Y. Nie (ORCID: https://orcid.org/0009-0005-0756-0275)
Institutions
- Fujian Medical University (CN)
- Central South University (CN)
- Xiamen University (CN)
- First Affiliated Hospital of Xiamen University (CN)
- Zhongshan Hospital of Xiamen University (CN)
- Second Xiangya Hospital of Central South University (CN)
- Union Hospital (CN)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-04-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.115487
- Citations
- 2
- Primary Topic
- Cancer-related gene regulation
- Type
- article
- Field-Weighted Citation Impact
- 1.61
Funders
- National Natural Science Foundation of China
- Ministry of Science and Technology of the People's Republic of China
- China Postdoctoral Science Foundation
- Science, Technology and Innovation Commission of Shenzhen Municipality
- Shantou University Medical College
- Fundamental Research Funds for the Central Universities