Interplay between arginine methylation and ubiquitylation regulates KLF4-mediated genome stability and carcinogenesis
Open accessAbstract
KLF4 is an important regulator of cell-fate decision, including DNA damage response and apoptosis. We identify a novel interplay between protein modifications in regulating KLF4 function. Here we show that arginine methylation of KLF4 by PRMT5 inhibits KLF4 ubiquitylation by VHL and thereby reduces KLF4 turnover, resulting in the elevation of KLF4 protein levels concomitant with increased transcription of KLF4-dependent p21 and reduced expression of KLF4-repressed Bax. Structure-based modelling and simulations provide insight into the molecular mechanisms of KLF4 recognition and catalysis by PRMT5. Following genotoxic stress, disruption of PRMT5-mediated KLF4 methylation leads to abrogation of KLF4 accumulation, which, in turn, attenuates cell cycle arrest. Mutating KLF4 methylation sites suppresses breast tumour initiation and progression, and immunohistochemical stain shows increased levels of both KLF4 and PRMT5 in breast cancer tissues. Taken together, our results point to a critical role for aberrant KLF4 regulation by PRMT5 in genome stability and breast carcinogenesis.
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PRMT5 has been implicated in driving neoplastic growth of multiple tumours including B cell lymphoma, multiple myeloma, breast cancer and glioblastoma.
“More recently, the arginine methyltransferase PRMT5 has been implicated in driving neoplastic growth of multiple tumours including B cell lymphoma, multiple myeloma, breast cancer and glioblastoma 171-178 .”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [178]
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- Authors
- Hu, D., Gur, M., Zhou, Z., Gamper, A., Hung, M.-C., Fujita, N., Lan, L., Bahar, I., & Wan, Y.
- Affiliations
- University of Pittsburgh (US)
- The University of Texas MD Anderson Cancer Center (US)
- Japanese Foundation For Cancer Research (JP)
- Corresponding author
- Wan, Yong
- Venue
- Nature Communications
- Published
- 2015-09-30
- Volume
- 6
- Issue
- 1
- Pages
- 8419-8419
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4598737
- OpenAlex
- W2265354786
- Cited by
- 154
- References
- 58
- Citations by year
- 2026: 15 · 2025: 15 · 2024: 14 · 2023: 15 · 2022: 15 · 2021: 19 · 2020: 12 · 2019: 23 · 2018: 8 · 2017: 12 · 2016: 5
- FWCI
- 3.62
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- University of Pittsburgh
- National Institutes of Health (UL1TR000005)
- National Human Genome Research Institute (U54HG008540)
- National Cancer Institute (CA154695, R01CA154695)
- National Institute of General Medical Sciences (R01GM086238)
- National Institute of Allergy and Infectious Diseases (U19AI068021, 5U19AI068021-6556)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Kruppel-like factors research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- KLF4, PRMT5, arginine methylation, ubiquitination, VHL, protein turnover, genome stability, breast cancer, carcinogenesis, p21, Bax, DNA damage response, cell cycle arrest, genotoxic stress
- MeSH terms
- Kruppel-Like Factor 4, Arginine, Breast Neoplasms, DNA Damage, Female, Humans, Methylation, Protein-Arginine N-Methyltransferases, Gene Expression Regulation, Neoplastic, Amino Acid Motifs, Genomic Instability, Cell Line, Tumor, Kruppel-Like Transcription Factors, Ubiquitination, Carcinogenesis
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