RESUMO
The folate-coupled metabolic enzyme MTHFD2 (the mitochondrial methylenetetrahydrofolate dehydrogenase/cyclohydrolase) confers redox homeostasis and drives cancer cell proliferation and migration. Here, we show that MTHFD2 is hyperacetylated and lysine 88 is the critical acetylated site. SIRT3, the major deacetylase in mitochondria, is responsible for MTHFD2 deacetylation. Interestingly, chemotherapeutic agent cisplatin inhibits expression of SIRT3 to induce acetylation of MTHFD2 in colorectal cancer cells. Cisplatin-induced acetylated K88 MTHFD2 is sufficient to inhibit its enzymatic activity and downregulate NADPH levels in colorectal cancer cells. Ac-K88-MTHFD2 is significantly decreased in human colorectal cancer samples and is inversely correlated with the upregulated expression of SIRT3. Our findings reveal an unknown regulation axis of cisplatin-SIRT3-MTHFD2 in redox homeostasis and suggest a potential therapeutic strategy for cancer treatments by targeting MTHFD2.
Assuntos
Cisplatino/metabolismo , Neoplasias Colorretais/metabolismo , Sirtuína 3/metabolismo , Acetilação , Aminoidrolases/genética , Aminoidrolases/metabolismo , Aminoidrolases/fisiologia , Antineoplásicos/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Cisplatino/farmacologia , Neoplasias do Colo/metabolismo , Neoplasias Colorretais/tratamento farmacológico , Ácido Fólico/metabolismo , Células HCT116 , Células HEK293 , Células HeLa , Humanos , Hidrolases , Metilenotetra-Hidrofolato Desidrogenase (NADP)/metabolismo , Metilenotetra-Hidrofolato Desidrogenase (NADP)/fisiologia , Mitocôndrias/metabolismo , Enzimas Multifuncionais/genética , Enzimas Multifuncionais/metabolismo , Enzimas Multifuncionais/fisiologia , OxirreduçãoRESUMO
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.