Ubiquitin-specific protease 21 is critical for mitochondrial function of cancer cells regulating their proliferation and migration

Ubiquitin Specific Peptidases (USPs) are the main members of deubiquitinases (DUBs) thatcatalyze removing ubiquitin molecules from target proteins, thereby modulating their half-lifeand function. Their enzymatic activity regulates protein degradation which is critical formaintaining cell homeostasis. Recently USP21 has been implicated in a process ofcarcinogenesis by regulation of oncogenic proteins. In our study, transcriptome and proteomedata from WT and USP21 KO HAP-1 cells revealed that endogenous USP21 is critical for genesand proteins involved in mitochondrial function. Further bioinformatic analysis demonstratedthat expression of USP21-dependent genes is controlled by STAT3 transcription factor.Subsequently, we found that the activity of STAT3 measured by its phosphorylation at Tyr705is a USP21-dependent process. These results prompted us to verify biological consequences ofgenetic deletion of USP21 on cellular metabolism and regulation of cancer progression. Weobserved a decreased oxygen consumption rate for all parameters of mitochondrial function anddisturbed ATP production in USP21 knock-out cells, which lead to the inhibition of theirproliferation and migration. Similar effects were observed in A549 cells with silencedexpression of USP21, suggesting that a novel role of USP21 in regulation of STAT-3 dependentmitochondrial energy may be a universal mechanism utilized by various cancers. Takentogether, our findings suggest that dysregulation of energy status and mitochondrial respirationof cancer cells by targeting USP21 is a promising approach in anti-cancer therapy.