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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Parkin ubiquitinates phosphoglycerate dehydrogenase to suppress serine synthesis and tumor progression

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 7

Parkin inhibits tumorigenesis through negative regulation of PHGDH.

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Parkin inhibits tumorigenesis through negative regulation of PHGDH. (A) ...
(A) Parkin KO promoted the growth of orthotopic breast tumors formed by Hs578T cells, which was greatly abolished by PHGDH KO. Left and middle: representative images of mice bearing tumors (left) and the collected tumors (middle) at day 34 after cell inoculation. Right: growth curves of tumors. Scale bars: 10 mm. n = 8. (B) IHC staining of Parkin, PHGDH, and Ki-67 in Hs578T orthotopic breast tumors described in A. Left panels: representative images. Scale bar: 20 μm. Right panel: percentage of Ki-67–positive cells in tumors. n = 6. (C) Levels of total serine and glycine in Hs578T orthotopic breast tumors described in A analyzed by LC-MS–based metabolomics analysis. n = 8. (D) Parkin KO promoted the growth of s.c. xenograft tumors formed by H1299 cells, which was greatly abolished by PHGDH KO in cells. n = 8. (E) Myc-Parkin expression in Hs578T cells inhibited the growth of orthotopic breast tumors, which was greatly abolished by PHGDH KO. n = 8. (F) Ectopic expression of K330R mutant PHGDH greatly abolished the inhibitory effect of Myc-Parkin on the growth of orthotopic breast tumors formed by PHGDH-KO Hs578T cells. n = 8. (G) Orthotopic breast tumors formed by Hs578T-Parkin-KO cells and s.c. tumors formed by H1299-Parkin-KO cells were more sensitive to NCT-503 treatment (i.p., 15 mg/kg; once daily for 4 weeks) compared with tumors formed by their control WT cells. n = 10. (H) Representative images of IHC staining of Parkin and PHGDH in human breast cancer specimens and lung cancer specimens. Scale bars: 20 μm. *P < 0.001; **P < 0.0001, mixed model analysis with Bonferroni’s adjusted P values for A and D–G and heterogeneous variance model with Dunnett’s adjusted P values for B and C.