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Parkin ubiquitinates phosphoglycerate dehydrogenase to suppress serine synthesis and tumor progression
Juan Liu, … , Wenwei Hu, Zhaohui Feng
Juan Liu, … , Wenwei Hu, Zhaohui Feng
Published May 18, 2020
Citation Information: J Clin Invest. 2020;130(6):3253-3269. https://doi.org/10.1172/JCI132876.
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Research Article Metabolism Oncology Article has an altmetric score of 6

Parkin ubiquitinates phosphoglycerate dehydrogenase to suppress serine synthesis and tumor progression

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Abstract

Phosphoglycerate dehydrogenase (PHGDH), the first rate-limiting enzyme of serine synthesis, is frequently overexpressed in human cancer. PHGDH overexpression activates serine synthesis to promote cancer progression. Currently, PHGDH regulation in normal cells and cancer is not well understood. Parkin, an E3 ubiquitin ligase involved in Parkinson’s disease, is a tumor suppressor. Parkin expression is frequently downregulated in many types of cancer, and its tumor-suppressive mechanism is poorly defined. Here, we show that PHGDH is a substrate for Parkin-mediated ubiquitination and degradation. Parkin interacted with PHGDH and ubiquitinated PHGDH at lysine 330, leading to PHGDH degradation to suppress serine synthesis. Parkin deficiency in cancer cells stabilized PHGDH and activated serine synthesis to promote cell proliferation and tumorigenesis, which was largely abolished by targeting PHGDH with RNA interference, CRISPR/Cas9 KO, or small-molecule PHGDH inhibitors. Furthermore, Parkin expression was inversely correlated with PHGDH expression in human breast cancer and lung cancer. Our results revealed PHGDH ubiquitination by Parkin as a crucial mechanism for PHGDH regulation that contributes to the tumor-suppressive function of Parkin and identified Parkin downregulation as a critical mechanism underlying PHGDH overexpression in cancer.

Authors

Juan Liu, Cen Zhang, Hao Wu, Xiao-Xin Sun, Yanchen Li, Shan Huang, Xuetian Yue, Shou-En Lu, Zhiyuan Shen, Xiaoyang Su, Eileen White, Bruce G. Haffty, Wenwei Hu, Zhaohui Feng

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Figure 5

Parkin inhibits serine synthesis in cells through negative regulation of PHGDH.

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Parkin inhibits serine synthesis in cells through negative regulation of...
(A) Schematic of U-13C-glucose incorporation into serine and glycine in cells. (B) Myc-Parkin expression reduced the incorporation of 13C into serine and glycine and the levels of total intracellular serine and glycine in Hs578T and H1299 cells, which was largely abolished by PHGDH knockdown. (C) Parkin knockdown increased the incorporation of 13C into serine and glycine and the levels of total serine and glycine in cells, which was largely abolished by PHGDH knockdown. (D) Parkin KO increased the incorporation of 13C into serine and glycine and the levels of total serine and glycine in cells, which was abolished by PHGDH KO. (E) Effects of Parkin mutants (C431A, T240M, and P294S) on the incorporation of 13C into serine and glycine and the levels of total serine and glycine in Hs578T cells. (F) PHGDH K330R mutation largely abolished the effect of Myc-Parkin on the incorporation of 13C into serine and glycine and the levels of total serine and glycine in PHGDH-KO Hs578T cells. (G) Parkin–/– MEFs displayed higher levels of 13C incorporation into serine and glycine as well as higher levels of total serine and glycine compared with Parkin+/+ MEFs. Three different MEF lines were used for assays. For B–G, cells were incubated with U-13C-glucose for 25 minutes for LC-MS analysis. (H) Parkin–/– mice displayed higher levels of serine and glycine in breast and lung tissues as well as serum compared with Parkin+/+ mice. Data are presented as mean ± SD. n = 3 for B, E–G; n = 5 for C, D; and n = 5 mice/group for H. #P < 0.05; ##P < 0.01; *P < 0.001; **P < 0.0001, heterogeneous variance model with Dunnett’s adjustment for multiple testing.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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