Cul4A-DDB1–mediated monoubiquitination of phosphoglycerate dehydrogenase promotes colorectal cancer metastasis via increased S-adenosylmethionine
Yajuan Zhang, … , Dawei Li, Weiwei Yang
Yajuan Zhang, … , Dawei Li, Weiwei Yang
Published November 1, 2021
Citation Information: J Clin Invest. 2021;131(21):e146187. https://doi.org/10.1172/JCI146187.
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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 6

Increased SAM levels by PHGDH K146mUb promote tumor cell migration by initiating SETD1A-mediated histone methylation of LAMC2 and CYR61.

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Increased SAM levels by PHGDH K146mUb promote tumor cell migration by in...
(A) HCT116 cells were transfected with siRNAs targeting nontargeting (NT), KMT2A, KMT2C, KMT2D, SETD1A, SETD1B, or SMYD3. ChIP analyses with anti-H3K4me3 antibody were performed. (B) PHGDH-depleted HCT116 cells rescued with rPHGDH WT or K146R were infected with or without the lentivirus expressing SETD1A or SETD1AΔSET. ChIP analyses were performed with anti-H3K4me3 antibody. (C and D) PHGDH-depleted HCT116 cells rescued with rPHGDH WT or K146R were infected with or without the lentivirus expressing SETD1A. Immunoblotting analyses were performed (C). Transwell migration assays were performed (D). (E and F) HCT116 cells were depleted of endogenous SETD1A and rescued with rSETD1A. LAMC2 and CYR61 expression was examined by immunoblotting analyses (E). Transwell migration assay was performed in these cells (F). (G) In vitro methylation assays were performed with purified recombinant His-tagged methyltransferase domains of KMT2A, KMT2C, KMT2D, SETD1A, SETD1B or SMYD3, SAM, and H3K4 peptide, followed by dot blot analysis with anti-H3K4me3 antibody. (H) ITC assays were performed with purified recombinant His-tagged methyltransferase domains of indicated HMTs and SAM. Representative images (left) and statistical results (right) of ITC were shown. (A, B, D, F, and H) Data represent the mean ± SD of 3 biologically independent experiments. One-way ANOVA with Tukey’s multiple-comparison test. **P < 0.01. See also Supplemental Figure 6.