RNA-seq of HAP1 wild type and USP-21 Knock-out cells
Ubiquitin Specific Peptidases (USPs) are the main members of deubiquitinases (DUBs) that  catalyze removing ubiquitin molecules from target proteins, thereby modulating their half-life  and function. Their enzymatic activity regulates protein degradation which is critical for maintaining cell homeostasis. Recently USP21 has been implicated in a process of  carcinogenesis by regulation of oncogenic proteins. In our study, transcriptome and proteome  data from WT and USP21 KO HAP-1 cells revealed that endogenous USP21 is critical for genes and proteins involved in mitochondrial function. Further bioinformatic analysis demonstrated that expression of USP21-dependent genes is controlled by STAT3 transcription factor. Subsequently, we found that the activity of STAT3 measured by its phosphorylation at Tyr705 is a USP21-dependent process. These results prompted us to verify biological consequences of  genetic deletion of USP21 on cellular metabolism and regulation of cancer progression. We  observed a decreased oxygen consumption rate for all parameters of mitochondrial function and  disturbed ATP production in USP21 knock-out cells, which lead to the inhibition of their  proliferation and migration. Similar effects were observed in A549 cells with silenced expression of USP21, suggesting that a novel role of USP21 in regulation of STAT-3 dependent  mitochondrial energy may be a universal mechanism utilized by various cancers. Taken  together, our findings suggest that dysregulation of energy status and mitochondrial respiration of cancer cells by targeting USP21 is a promising approach in anti-cancer therapy.