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PRMT1 Sustains De Novo Fatty Acid Synthesis by Methylating PHGDH to Drive Chemoresistance in Triple-Negative Breast
Takehiro Yamamoto1, Tetsu Hayashida2, Yohei Masugi3
1Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan.
Abstract:
Triple-negative breast cancer (TNBC) chemoresistance hampers the ability to effectively treat patients. Identification of mechanisms driving chemoresistance can lead to strategies to improve treatment. Here, we revealed that protein arginine methyltransferase-1 (PRMT1) simultaneously methylates D-3-phosphoglycerate dehydrogenase (PHGDH), a critical enzyme in serine synthesis, and the glycolytic enzymes PFKFB3 and PKM2 in TNBC cells. 13C metabolic flux analyses showed that PRMT1-dependent methylation of these three enzymes diverts glucose toward intermediates in the serine-synthesizing and serine/glycine cleavage pathways, thereby accelerating the production of methyl donors in TNBC cells. Mechanistically, PRMT1-dependent methylation of PHGDH at R54 or R20 activated its enzymatic activity by stabilizing 3-phosphoglycerate binding and suppressing polyubiquitination. PRMT1-mediated PHGDH methylation drove chemoresistance independently of glutathione synthesis. Rather, activation of the serine synthesis pathway supplied α-ketoglutarate and citrate to increase palmitate levels through activation of fatty acid synthase (FASN). Increased palmitate induced protein S-palmitoylation of PHGDH and FASN to further enhance fatty acid synthesis in a PRMT1-dependent manner. Loss of PRMT1 or pharmacologic inhibition of FASN or protein S-palmitoyltransferase reversed chemoresistance in TNBC. Furthermore, IHC coupled with imaging MS in clinical TNBC specimens substantiated that PRMT1-mediated methylation of PHGDH, PFKFB3, and PKM2 correlates with chemoresistance and that metabolites required for methylation and fatty acid synthesis are enriched in TNBC. Together, these results suggest that enhanced de novo fatty acid synthesis mediated by coordinated protein arginine methylation and protein S-palmitoylation is a therapeutic target for overcoming chemoresistance in TNBC.
Significance:
PRMT1 promotes chemoresistance in TNBC by methylating metabolic enzymes PFKFB3, PKM2, and PHGDH to augment de novo fatty acid synthesis, indicating that targeting this axis is a potential treatment strategy.
Insights
Protein arginine methyltransferase-1 (PRMT1) drives chemoresistance in triple-negative breast cancer (TNBC) by boosting fatty acid synthesis. Inhibiting PRMT1 or fatty acid synthesis can overcome this resistance.
Area of Science:
- Metabolic pathways and enzyme regulation in cancer
- Cancer cell metabolism
- Biochemistry and molecular biology
Background:
- Triple-negative breast cancer (TNBC) exhibits significant chemoresistance, limiting effective treatment options.
- Understanding the molecular mechanisms underlying TNBC chemoresistance is crucial for developing novel therapeutic strategies.
- Metabolic reprogramming plays a key role in cancer progression and treatment resistance.
Purpose of the Study:
- To elucidate the role of protein arginine methyltransferase-1 (PRMT1) in mediating chemoresistance in TNBC.
- To identify the specific metabolic enzymes targeted by PRMT1 in TNBC cells.
- To investigate the downstream consequences of PRMT1-mediated metabolic alterations on chemoresistance.
Main Methods:
- Utilized 13C metabolic flux analysis to track glucose metabolism.
- Employed biochemical assays to assess enzyme activity and protein modifications (methylation, S-palmitoylation).
- Investigated the effects of genetic (PRMT1 knockout) and pharmacologic inhibition (FASN, protein S-palmitoyltransferase inhibitors) on TNBC chemoresistance.
- Analyzed clinical TNBC specimens using immunohistochemistry (IHC) and imaging mass spectrometry (MS).
Main Results:
- PRMT1 methylates metabolic enzymes PHGDH, PFKFB3, and PKM2, diverting glucose towards serine synthesis and methyl donor production.
- PRMT1-mediated PHGDH methylation enhances its enzymatic activity and stability, promoting de novo fatty acid synthesis via FASN activation.
- Inhibition of PRMT1, FASN, or protein S-palmitoyltransferase reversed chemoresistance in TNBC models.
- Clinical TNBC samples showed elevated PRMT1-mediated methylation of target enzymes and enriched metabolites associated with methylation and fatty acid synthesis.
Conclusions:
- PRMT1 promotes TNBC chemoresistance by coordinating protein arginine methylation and S-palmitoylation to enhance de novo fatty acid synthesis.
- Targeting the PRMT1-mediated metabolic axis represents a promising therapeutic strategy for overcoming chemoresistance in TNBC.
- The findings highlight a novel mechanism linking metabolic enzyme methylation to lipid synthesis and cancer drug resistance.
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