Cul4A-DDB1–mediated monoubiquitination of phosphoglycerate dehydrogenase promotes colorectal cancer metastasis via increased S-adenosylmethionine
Yajuan Zhang, Hua Yu, Jie Zhang, Hong Gao, Siyao Wang, Shuxian Li, Ping Wei, Ji Liang, Guanzhen Yu, Xiongjun Wang, Xinxiang Li, Dawei Li, Weiwei Yang
Yajuan Zhang, Hua Yu, Jie Zhang, Hong Gao, Siyao Wang, Shuxian Li, Ping Wei, Ji Liang, Guanzhen Yu, Xiongjun Wang, Xinxiang Li, Dawei Li, Weiwei Yang
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Research Article Metabolism Oncology

Cul4A-DDB1–mediated monoubiquitination of phosphoglycerate dehydrogenase promotes colorectal cancer metastasis via increased S-adenosylmethionine

Abstract

Although serine metabolism plays a crucial role in the proliferation and survival of tumor cells, how it supports tumor cell migration remains poorly understood. Phosphoglycerate dehydrogenase (PHGDH) catalyzes the oxidation of 3-phosphoglycerate to 3-phosphonooxypyruvate, the first committed step in de novo serine biosynthesis. Here we show that PHGDH was monoubiquitinated by cullin 4A–based E3 ligase complex at lysine 146 in colorectal cancer (CRC) cells, which enhanced PHGDH activity by recruiting a chaperone protein, DnaJ homolog subfamily A member 1, to promote its tetrameric formation, thereby increasing the levels of serine, glycine, and S-adenosylmethionine (SAM). Increased levels of SAM upregulated the expression of cell adhesion genes (laminin subunit gamma 2 and cysteine rich angiogenic inducer 61) by initiating SET domain containing 1A–mediated trimethylation of histone H3K4, thereby promoting tumor cell migration and CRC metastasis. Intriguingly, SAM levels in tumors or blood samples correlated with the metastatic recurrence of patients with CRC. Our finding not only reveals a potentially new role and mechanism of SAM-promoted tumor metastasis but also demonstrates a regulatory mechanism of PHGDH activity by monoubiquitination.

Authors

Yajuan Zhang, Hua Yu, Jie Zhang, Hong Gao, Siyao Wang, Shuxian Li, Ping Wei, Ji Liang, Guanzhen Yu, Xiongjun Wang, Xinxiang Li, Dawei Li, Weiwei Yang

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Figure 5

PHGDH K146mUb upregulates cell adhesion gene expression and promotes tumor cell migration.

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PHGDH K146mUb upregulates cell adhesion gene expression and promotes tum...
(A) RNA-sequencing analyses were performed in HCT116 cells stably expressing shNT or shPHGDH. GO enrichment analyses were presented. (B and C) PHGDH-depleted HCT116 cells rescued with rPHGDH WT or K146R were treated with or without SAM (25 μM) for 12 hours. The mRNA levels (B) and protein levels (C) of LAMC2 and CYR61 were examined. (D) PHGDH-depleted HCT116 cells rescued with rPHGDH WT or K146R were harvested. ChIP-PCR analyses with anti-H3K4me3 antibody were performed. (E) PHGDH-depleted HCT116 cells rescued with rPHGDH WT or K146R were infected with or without the lentivirus expressing both LAMC2 and CYR61. Transwell migration assays were performed. Representative images (top) and statistical analyses (bottom) of the migrated cells were shown. One-way ANOVA with Tukey’s multiple-comparison test. (F and G) HCT116 cells were treated with or without SAM (100 μM). ChIP analyses with anti-H3K4me3 antibody (F) and real-time PCR analysis (G) were performed. (B, D–G) Data represent the mean ± SD of 3 biologically independent experiments. (B, D, F, and G) 2-tailed Student’s t test. **P < 0.01. See also Supplemental Figure 5.