PHGDH arginine methylation by PRMT1 promotes serine synthesis and represents a therapeutic vulnerability in hepatocellular carcinoma

Wang, Kui; Luo, Li; Fu, Shuyue; Wang, Mao; Wang, Zihao; Dong, Lixia; Wu, Xingyun; Dai, Lunzhi; Peng, Yong; Shen, Guobo; Chen, Hai‐Ning; Nice, Edouard C.; Wei, Xiawei; Huang, Canhua

doi:10.1038/s41467-023-36708-5

Cited by 40 publications

(23 citation statements)

References 72 publications

(131 reference statements)

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“…These findings underscore the effectiveness of PRMT1 inhibition as a promising strategy for MM therapy, particularly in relapsed/refractory cases where alternative treatment options are limited. GSK3368715 is a potent oral PRMT type I inhibitor that exhibits strong anti-cancer activity in vivo in many preclinical models (29)(30)(31). This inhibitor was used in the clinical trial for solid tumors and diffused large B-cell lymphoma (NCT03666988).…”

Section: Discussionmentioning

confidence: 99%

Protein arginine methyltransferase 1 is a therapeutic vulnerability in multiple myeloma

Nguyen

Liu

et al. 2023

Front. Immunol.

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Multiple myeloma (MM) is a devastating plasma cell malignancy characterized by the expansion of aberrant monoclonal plasma cells in the bone marrow, leading to severe clinical manifestations and poor prognosis, particularly in relapsed/refractory cases. Identifying novel therapeutic targets is crucial to improve treatment outcomes in these patients. In this study, we investigated the role of the protein arginine methyltransferase 1 (PRMT1) in MM pathogenesis and explored its potential as a therapeutic target. We observed that PRMT1, responsible for most asymmetric di-methylation in cells, exhibited the highest expression among PRMT family members in MM cell lines and primary MM cells. Importantly, PRMT1 expression was significantly elevated in relapsed/refractory patients compared to newly diagnosed patients. High expression of PRMT1 expression was strongly associated with poor prognosis. We found that genetic or enzymatic inhibition of PRMT1 impaired MM cell growth, induced cell cycle arrest, and triggered cell death. Treatment with MS023, a potent PRMT type I inhibitor, demonstrated a robust inhibitory effect on the viability of primary cells isolated from newly diagnosed and proteasome inhibitor-relapsed/refractory patients in a dose-dependent manner. Suppression of PRMT1 downregulated genes related to cell division and upregulated genes associated with apoptosis pathway. We also found that genes related to immune response and lymphocyte activation were significantly upregulated in PRMT1-suppressed cells. Notably, the activation status of T cells was strikingly enhanced upon co-culturing with PRMT1-KO MM cells. In vivo studies using a xenograft model revealed that targeting PRMT1 by either CRISPR/Cas9-mediated knockout or MS023 treatment significantly attenuated MM tumor growth and prolonged the survival of tumor-bearing mice. Histological analysis further confirmed increased apoptotic cell death in MS023-treated tumors. Collectively, our findings establish PRMT1 as an indispensable and novel therapeutic vulnerability in MM. The elevated expression of PRMT1 in relapsed/refractory patients underscores its potential as a target for overcoming treatment resistance. Moreover, our results highlight the efficacy of MS023 as a promising therapeutic agent against MM, offering new avenues for therapeutic approaches in relapsed/refractory MM.

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Section: Discussionmentioning

confidence: 99%

Protein arginine methyltransferase 1 is a therapeutic vulnerability in multiple myeloma

Nguyen

Liu

et al. 2023

Front. Immunol.

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“…Another research group reported that the activation of PHGDH through the monomethylation of different arginine residue R236 (located at the substrate recognition site) by PRMT1 shunts into the glutathione synthetic pathway to reduce ROS levels for hepatocellular carcinoma progression ( 57 ). However, our results indicate a glutathione-independent mechanism to acquire chemoresistance of TNBC ( Fig.…”

Section: Discussionmentioning

confidence: 99%

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

Yamamoto,

Hayashida,

Masugi

et al. 2024

Cancer Research

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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 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 pharmacological inhibition of FASN or protein S-palmitoyltransferase reversed chemoresistance in TNBC. Furthermore, immunohistochemistry coupled with imaging mass spectrometry 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.

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“…PRMT1, the first identified arginine methyltransferase, plays a crucial role in a range of biological processes, including the cell cycle, DNA damage, transcription and signal transduction [6] . Recent studies have demonstrated a regulatory role of PRMT1 in cellular metabolic pathways, including serine metabolism [7] , lipid metabolism [8,9] and glucose homeostasis [10][11][12] . In addition, high PRMT1 expression is known to contribute to cell proliferation in multiple tumors [13][14][15] .…”

Section: Introductionmentioning

confidence: 99%

PRMT1 promotes Warburg effect by regulating the PKM2/PKM1 ratio in Non-small cell lung cancer

Lu,

Peng,

Zhao

et al. 2024

Preprint

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Abnormal epigenetic modifications are involved in the regulation of Warburg effect in tumor cells. Protein arginine methyltransferases (PRMTs) mediate arginine methylation and have critical functions in cellular responses. PRMTs are deregulated in a variety of cancers, but their precise roles in Warburg effect in cancer is largely unknown. Experiments from the current study showed that PRMT1 was highly expressed under conditions of glucose sufficiency. PRMT1 induced an increase in the PKM2/PKM1 ratio through upregulation of PTBP1, in turn, promoting aerobic glycolysis in non-small cell lung cancer (NSCLC). The PRMT1 level in p53-deficient and p53-mutated NSCLC remained relatively unchanged while the expression was reduced in p53 wild-type NSCLC under conditions of glucose insufficiency. Notably, p53 activation under glucose-deficient conditions could suppress USP7 and further accelerate the polyubiquitin-dependent degradation of PRMT1. Melatonin, a hormone that inhibits glucose intake, markedly suppressed cell proliferation of p53 wild-type NSCLC, while a combination of melatonin and the USP7 inhibitor P5091 enhanced the anticancer activity in p53-deficient NSCLC. Our collective findings support a role of PRMT1 in the regulation of Warburg effect in NSCLC. Moreover, combination treatment with melatonin and the USP7 inhibitor showed good efficacy, providing a rationale for the development of PRMT1-based therapy to improve p53-deficient NSCLC outcomes.

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PHGDH arginine methylation by PRMT1 promotes serine synthesis and represents a therapeutic vulnerability in hepatocellular carcinoma

Cited by 40 publications

References 72 publications

Protein arginine methyltransferase 1 is a therapeutic vulnerability in multiple myeloma

Protein arginine methyltransferase 1 is a therapeutic vulnerability in multiple myeloma

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

PRMT1 promotes Warburg effect by regulating the PKM2/PKM1 ratio in Non-small cell lung cancer

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