FBXO7 ubiquitinates PRMT1 to suppress serine synthesis and tumor growth in hepatocellular carcinoma

Abstract

Cancer cells are often addicted to serine synthesis to support growth. How serine synthesis is regulated in cancer is not well understood. We recently demonstrated protein arginine methyltransferase 1 (PRMT1) is upregulated in hepatocellular carcinoma (HCC) to methylate and activate phosphoglycerate dehydrogenase (PHGDH), thereby promoting serine synthesis. However, the mechanisms underlying PRMT1 upregulation and regulation of PRMT1-PHGDH axis remain unclear. Here, we show the E3 ubiquitin ligase F-box-only protein 7 (FBXO7) inhibits serine synthesis in HCC by binding PRMT1, inducing lysine 37 ubiquitination, and promoting proteosomal degradation of PRMT1. FBXO7-mediated PRMT1 downregulation cripples PHGDH arginine methylation and activation, resulting in impaired serine synthesis, accumulation of reactive oxygen species (ROS), and inhibition of HCC cell growth. Notably, FBXO7 is significantly downregulated in human HCC tissues, and inversely associated with PRMT1 protein and PHGDH methylation level. Overall, our study provides mechanistic insights into the regulation of cancer serine synthesis by FBXO7-PRMT1-PHGDH axis, and will facilitate the development of serine-targeting strategies for cancer therapy.

The Interplay of Acetylation and Ubiquitination Controls PRMT1 Homeostasis

“…2D). Similar to the literature (Luo et al, 2024), we observed that PRMT1 has a relatively long half-life of approximately 15 hours when unperturbed, which is significantly shortened by p300 overexpression and extended by p300 inhibition (Fig. 2D).…”

“…Given the importance of PRMT1 homeostasis to cellular arginine methylation, there are multiple mechanisms by which PRMT1 can be degraded. For example, it has also been reported to be modulated by other E3 ligases, including TRIM48 (Hirata et al, 2017) and FBXO7 (Luo et al ., 2024). Excitingly, both the TRIM48-PRMT1 and FBXO7-PRMT1 interactions are preliminarily evidenced to be viable therapeutic targets for inhibiting oncogenic metabolism exhibited by hepatocellular carcinoma (Li et al ., 2023; Luo et al ., 2024).…”

“…For example, it has also been reported to be modulated by other E3 ligases, including TRIM48 (Hirata et al, 2017) and FBXO7 (Luo et al ., 2024). Excitingly, both the TRIM48-PRMT1 and FBXO7-PRMT1 interactions are preliminarily evidenced to be viable therapeutic targets for inhibiting oncogenic metabolism exhibited by hepatocellular carcinoma (Li et al ., 2023; Luo et al ., 2024). Our findings supplement the growing landscape of PRMT1 homeostasis by providing evidence for a relationship between PRMT1s p300-mediated acetylation and its FBXL17-mediated ubiquitination and degradation.…”