PRMT1 Sustains De Novo Fatty Acid Synthesis by Methylating PHGDH to Drive Chemoresistance in Triple-Negative Breast Cancer.

Makoto Suematsu, Kenichi Horisawa, Masatoshi Wakui, Naoharu Takano, Minako Takizawa, Misa Nagasaka, Tomokazu Kurahori, Yujiro Yoshioka, Arisa Yamamoto, Yoshiko Naito, Masami Suzuki, Chiyoko Nishime, Mai Itoh, Noriyo Hayakawa, Kiyotaka Oshikawa, Tetsu Hayashida, Akiko Kubo, Takako Hishiki, Yuko Kitagawa, Atsushi Suzuki, Tomomi Matsuura, Yohei Masugi, Yasuaki Kabe, Koji Kawakami, Takushi Yamamoto, Michiie Sakamoto, Masaki Matsumoto, Yuko Kawai, Takehiro Yamamoto, Aiko Nagayama

Journal: Cancer research 2024;84(7):1065-1083

PMID: 38383964

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Abstract

UNLABELLED

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.

Address: Department of Biochemistry, Keio University School of Medicine, Tokyo, Japan.; Department of Surgery, Keio University School of Medicine, Tokyo, Japan.; Department of Pathology, Keio University School of Medicine, Tokyo, Japan.; Department of Omics and Systems Biology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.; Central Institute for Experimental Medicine and Life Science, Kawasaki, Japan.; Clinical Translational Research Center, Keio University Hospital, Tokyo, Japan.; Department of Laboratory Medicine, Keio University School of Medicine, Tokyo, Japan.; Solutions COE Analytical & Measuring Instruments Division, Shimadzu Corporation, Kyoto, Japan.; Division of Organogenesis and Regeneration, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.; Central Institute for Experimental Medicine and Life Science, Kawasaki, Japan.; Keio University WPI-Bio2Q Research Center, Tokyo, Japan.

DOI: 10.1158/0008-5472.CAN-23-2266