Objective: To explore the neddylation pathway, found to be highly activated in various cancers, as a potential therapeutic target in endometrial carcinoma, one of the three most frequent malignant tumours in the female reproductive system.
Methods: Data from The Cancer Genome Atlas were analysed using online servers. Expression levels of key neddylation genes were validated by reverse-transcription polymerase chain reaction and western blots of tumour and adjacent tissues. Underlying mechanisms and the effects on cell activities of the neddylation pathway-specific inhibitor, MLN4924, were investigated in endometrial cancer cell lines.
Results: Key neddylation enzymes, ubiquitin conjugating enzyme E2 M (UBC12), ubiquitin conjugating enzyme E2 F (UBE2F), ring-box 1 (RBX1) and ring finger protein 7 (RBX2), were significantly overexpressed in endometrial carcinoma tissues versus normal tissues, but only UBE2F and RBX2 positively correlated with patient survival. MLN4924 significantly suppressed proliferation and colony formation in EC cells by inducing DNA re-replication, cell cycle arrest and apoptosis. Mechanism study revealed that MLN4924 induced the accumulation of cullin-RING ligase substrates in vitro.
Conclusions: The neddylation pathway was identified to play an important role in endometrial cancer. The neddylation specific inhibitor, MLN4924, may be a potential therapeutic drug for endometrial carcinoma.
Keywords: Endometrial cancer; MLN4924; apoptosis; cell cycle arrest; cullin-RING ligase; neddylation.