Acetylation Stabilizes Phosphoglycerate Dehydrogenase by Disrupting the Interaction of E3 Ligase RNF5 to Promote Breast Tumorigenesis

• Published in: Cell reports (Cambridge) 2020-08, Vol.32 (6), p.108021-108021, Article 108021
• Main Authors: Wang, Chao, Wan, Xingyou, Yu, Tong, Huang, Zhenyu, Shen, Chao, Qi, Qian, Xiang, Sheng, Chen, Xinyuan, Arbely, Eyal, Ling, Zhi-Qiang, Liu, Chen-Ying, Yu, Wei
• Format: Article
• Language: English
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.108021

Phosphoglycerate dehydrogenase (PHGDH) is the first enzyme in the serine synthesis pathway in which it is also the rate-limiting enzyme. It is significantly upregulated in many cancers, especially breast cancer. However, the posttranslational mechanism of PHGDH upregulation in breast cancer is unknown. In this study, we find that RNF5, an E3 ubiquitin ligase, is essential for the degradation of PHGDH protein. PHGDH is degraded by RNF5 to prevent the proliferation of breast cancer cells. The acetylation of PHGDH at K58 is able to disrupt the interaction of RNF5-PHGDH and promote the proliferation of breast cancer cells. Tip60 and SIRT2 regulate the reversible acetylation modification of PHGDH in response to glucose alteration. Moreover, PHGDH is significantly upregulated in samples of human breast cancer and is associated with decreased RNF5 expression. This implies a potential therapeutic target through the interference interaction of PHGDH-RNF5 to degrade PHGDH in breast cancer. [Display omitted] •RNF5-mediated degradation of PHGDH prevents the proliferation of breast cancer cells•The acetylation of PHGDH at K58 disrupts the interaction of RNF5-PHGDH•SIRT2 and Tip60 regulate the reversible acetylation modification of PHGDH•PHGDH is negatively correlated with RNF5 in human breast cancer Wang et al. find that an E3 ubiquitin ligase, RNF5, promotes the ubiquitination and degradation of PHGDH protein. Acetylation is identified as a regulating signal in RNF5-mediated PHGDH degradation and is responsible for PHGDH protein accumulation. These findings provide a potential explanation for PHGDH overexpression in human cancers.