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Parkin on serine: a Parkinson disease gene suppresses serine synthesis in cancer
W. Brian Dalton
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
Address correspondence to: W. Brian Dalton, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 1650 Orleans Street, CRBI Room 285, Baltimore, Maryland 21231, USA. Phone: 410.614.6173; Email: wdalton2@jhmi.edu.
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Published May 18, 2020 - More info
J Clin Invest. 2020;130(6):2820–2822. https://doi.org/10.1172/JCI137411.
© 2020 American Society for Clinical Investigation
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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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A mutated ubiquitin ligase
In this issue of the JCI, Liu et al. (13) report a unique mechanism of PHGDH regulation by the Parkin (or PRKN) gene, a ubiquitin ligase that is mutated in a tumor-suppressor pattern in several cancer types (Figure 1). The authors started with a mass spectrometry screen of PHGDH-binding partners and found that the IBR domain of Parkin bound the SBD2 domain of PHGDH. This interaction was accompanied by ubiquitination of PHGDH at lysine 330 by Parkin, and this ubiquitination catalyzed the degradation of PHGDH in human cancer cell lines. The researchers then showed that degradation of PHGDH protein by Parkin suppressed serine synthesis, inhibited cell proliferation, and restrained growth of human cancer cell lines as xenografts in immunodeficient mice. Finally, the authors reported that human cancer cell lines with knockout of Parkin exhibited increased sensitivity to small molecule inhibitors of PHGDH, including the bioavailable compound NCT-503, which preferentially inhibited the growth of Parkin-knockout tumors in vivo (13).
Figure 1Proposed mechanism for how Parkin suppresses serine synthesis and tumor growth. (A) Tumors with intact Parkin target PHGDH for degradation, restricting intracellular serine synthesis and tumor growth. (B) Tumors lacking Parkin (due to knockout) have elevated PHGDH, serine synthesis, and tumor growth. (C) Targeting PHGDH with the small molecule NCT-503 inhibits serine synthesis and growth of Parkin knockout tumors.
Liu et al. (13) make several interesting contributions to our understanding of cancer metabolism. First, the authors identify a unique mode of SSP regulation through the ubiquitination of PHGDH. A previous study reported that PHGDH protein levels are positively regulated by the deubiquinating enzyme JOSD2, suggesting that differential activity of this enzyme may account for different levels of PHGDH protein in lung adenocarcinoma (14). The present work (13) reveals the opposing regulation — ubiquitination — expanding the known toolkit by which cells can regulate the SSP and by which cancer cells can disrupt it. It will be interesting for future studies to determine the extent to which cancers actually use this mechanism to upregulate the SSP. Moreover, given recent literature showing upregulation of the SSP upon acquired resistance to different cancer therapies, it would be interesting to determine whether higher PHGDH ever results from adaptive changes in JOSD2 or Parkin activity in these contexts (15–17).
Second, Liu et al. (13) identify a hitherto unknown oncogenic property of Parkin, a tumor-suppressor gene whose downstream mediators of oncogenesis are not well understood (13). Reprogramming of serine metabolism now joins other processes whose disruption by Parkin may be tumorigenic, such as cell cycle regulation, apoptosis, and mitophagy (18, 19). Inactivating mutations in Parkin are recurrent in a variety of human tumors, and inactivation of Parkin promotes tumor formation in genetically engineered mouse models (GEMMs) (20–22). While the authors focused here on human cancer cell line models, it will be interesting for future studies to determine the role that modulating serine synthesis has in the tumor properties of patient-derived xenografts (PDXs) with naturally arising Parkin mutations — and in GEMMs.
Third, in finding that cancer cell lines with Parkin knockout show increased sensitivity to PHGDH inhibition in vivo, Liu et al. (13) provide evidence that metabolic rewiring by Parkin downregulation forces a targetable dependence on the SSP. By extension, dependence on the SSP suggests that Parkin mutation status could provide a biomarker for tumors to be targeted in any eventual clinical trials of inhibitors of the SSP. As above with tumorigenicity, however, it would be important to first determine whether PHGDH inhibitors show activity against PDX models of human tumors with naturally occurring Parkin mutations. In addition, recent evidence shows that proliferation of cells with an upregulated SSP are constrained by availability of the electron acceptor NAD+, conferring a heightened sensitivity to small molecule inhibitors of the NAD+ salvage pathway enzyme NAMPT (23, 24). It could therefore be of interest to determine whether tumors with Parkin mutation are likewise sensitive to these inhibitors.
Finally, as Parkin mutations are causatively implicated in cases of autosomal recessive juvenile Parkinson disease (PD), the authors note that it is possible that deregulation of the SSP might have a role in PD pathophysiology (25).
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