Abstract
Krüppel-like factor 5 (KLF5) is an oncogenic factor that is highly expressed in basal-like breast cancer (BLBC) and promotes cell proliferation, survival, migration, stemness, and tumor growth; however, its posttranslational modifications are poorly defined. Protein arginine methyltransferase 5 (PRMT5) is also an oncogene implicated in various carcinomas, including breast cancer. In this study, we found that PRMT5 interacts with KLF5 and catalyzes the di-methylation of KLF5 at Arginine 57 (R57) in a methyltransferase activity-dependent manner in BLBC cells. Depletion or pharmaceutical inhibition (using PJ-68) of PRMT5 decreased the expression of KLF5 and its downstream target genes in vitro and in vivo. PRMT5-induced KLF5R57me2 antagonizes GSK3β-mediated KLF5 phosphorylation and subsequently Fbw7-mediated KLF5 ubiquitination and coupled degradation. Functionally, PRMT5 promotes breast cancer stem cell maintenance and proliferation, at least partially, by stabilizing KLF5. PRMT5 and KLF5 protein levels were positively correlated in clinical BLBCs. Taken together, PRMT5 methylates KLF5 to prevent its phosphorylation, ubiquitination, and degradation, and thus promotes breast cancer stem cell maintenance and proliferation. These findings suggest that PRMT5 is a potential therapeutic target for BLBC.
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All data generated and analyzed during this study are included in this published article. The datasets supporting the conclusions of this article are included within the article and its additional files.
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We thank all members of the laboratory for their help.
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This work was supported by the National Key Research and Development Program of China (2020YFA0112300 and 2018YFC2000400 to CC), National Natural Science Foundation of China (31771516 and 81830087 to CC; 81802671 and 81872414 to DJ), Yunnan Fundamental Research Projects (2019FB112 and 202001AW070018 to DJ), and Project of Innovative Research Team of Yunnan Province (2019HC005).
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CC and DJ were responsible for the conception and design and study supervision. XW and TQ were responsible for the development of the methodology, analysis and interpretation of the data, and experiments in vivo. CY, YW, and YS were responsible for the development of IHC. XW, TQ, CC, GD, YH, WL, and RL were responsible for the experiments in vitro. XW, TQ, DJ, and CC wrote and discussed the manuscript.
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Wang, X., Qiu, T., Wu, Y. et al. Arginine methyltransferase PRMT5 methylates and stabilizes KLF5 via decreasing its phosphorylation and ubiquitination to promote basal-like breast cancer. Cell Death Differ 28, 2931–2945 (2021). https://doi.org/10.1038/s41418-021-00793-0
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DOI: https://doi.org/10.1038/s41418-021-00793-0
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