Parkin ubiquitinates phosphoglycerate dehydrogenase to suppress serine synthesis and tumor progression
Parkin ubiquitinates phosphoglycerate dehydrogenase to suppress serine synthesis and tumor progression
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DOI：
10.1172/jci132876
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发表时间：
2020-06-01
影响因子：
15.9
通讯作者：
Feng, Zhaohui
中科院分区：
文献类型：
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作者：
Liu, Juan;Zhang, Cen;Feng, Zhaohui
作为丝氨酸合成的第一限速酶，磷酸甘油酸脱氢酶在人类癌症中经常过表达。PHGDH过表达激活丝氨酸合成，促进癌症进展。目前，PHGDH在正常细胞和癌症中的调控还不是很清楚。Parkin是一种与帕金森病有关的E3泛素连接酶，是一种肿瘤抑制因子。在许多类型的癌症中，Parkin的表达经常下调，其肿瘤抑制机制尚不清楚。在这里，我们表明PHGDH是Parkin介导的泛素化和降解的底物。Parkin与PHGDH相互作用，并在赖氨酸330位泛素化PHGDH，导致PHGDH降解以抑制丝氨酸合成。癌细胞中的Parkin缺陷稳定了PHGDH并激活了丝氨酸合成以促进细胞增殖和肿瘤发生，这在很大程度上被RNA干扰、CRISPR/Cas9 KO或小分子PHGDH抑制剂靶向PHGDH所消除。此外，在乳腺癌和肺癌中，Parkin的表达与PHGDH的表达呈负相关。我们的结果表明，Parkin泛素化PHGDH是PHGDH调节的关键机制，有助于Parkin的肿瘤抑制功能，并发现Parkin下调是PHGDH在癌症中过表达的关键机制。
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.