A cancer ubiquitome landscape identifies metabolic reprogramming as target of Parkin tumor suppression

Changes in metabolism that affect mitochondrial and glycolytic networks are hallmarks of cancer, but their impact in disease is still elusive. Using global proteomics and ubiquitome screens, we now show that Parkin, an E3 ubiquitin ligase and key effector of mitophagy altered in Parkinson's disease, shuts off mitochondrial dynamics and inhibits the non-oxidative phase of the pentose phosphate pathway. This blocks tumor cell movements, creates metabolic and oxidative stress, and inhibits primary and metastatic tumor growth. Uniformly down-regulated in cancer patients, Parkin tumor suppression requires its E3 ligase function, is reversed by antioxidants, and is independent of mitophagy. These data demonstrate that cancer metabolic networks are potent oncogenes directly targeted by endogenous tumor suppression.

Automated summary

Parkin, an E3 ubiquitin ligase altered in Parkinson's disease, is shown to suppress tumor growth by shutting off mitochondrial dynamics and inhibiting the non-oxidative phase of the pentose phosphate pathway. This tumor suppression function of Parkin requires its E3 ligase activity and can be reversed by antioxidants, independently of mitophagy. Cancer metabolic networks are identified as potential oncogenes directly targeted by endogenous tumor suppression mechanisms.