Arginine methyltransferase PRMT5 methylates and stabilizes KLF5 via decreasing its phosphorylation and ubiquitination to promote basal-like breast cancer.

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.

• Authors: Xinye Wang, Ting Qiu, Yingying Wu, Chuanyu Yang, Yi Li, Guangshi Du, Yaohui He, Wen Liu, Rong Liu, Chuan-Huizi Chen, Yujie Shi, Jingxuan Pan, Jia Zhou, Dewei Jiang, Ceshi Chen
• Journal: Cell death and differentiation (Cell Death Differ) Vol. 28 Issue 10 Pg. 2931-2945 (10 2021) ISSN: 1476-5403 [Electronic] England
• PMID: 33972717 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s), under exclusive licence to ADMC Associazione Differenziamento e Morte Cellulare.

Chemical References

• KLF5 protein, human
• Kruppel-Like Transcription Factors
• PRMT5 protein, human
• Protein-Arginine N-Methyltransferases

Topics

• Animals
• Breast Neoplasms (enzymology, metabolism, pathology)
• Cell Line, Tumor
• Cell Proliferation (physiology)
• Female
• Heterografts
• Humans
• Kruppel-Like Transcription Factors (metabolism)
• Methylation
• Mice
• Mice, Nude
• Phosphorylation
• Protein-Arginine N-Methyltransferases (metabolism)
• Transfection