Deubiquitinase USP9X regulates the invasion of prostate cancer cells by regulating the ERK pathway and mitochondrial dynamics

Abstract

The ubiquitin-specific protease 9X (USP9X) is a conserved deubiquitinase that has been investigated in several types of human cancer. However, the clinical significance and the biological roles of USP9X in prostate cancer remain unexplored. In the present study, an investigation into the expression and clinical significance of USP9X in prostate cancer revealed that USP9X expression was downregulated in prostate cancer tissues compared with that in healthy tissues. In addition, decreased USP9X expression was associated with a higher Gleason score and local invasion. Depletion of USP9X in prostate cancer LNCaP and PC-3 cells by small interfering RNA promoted cell invasion and migration. Furthermore, USP9X depletion upregulated matrix metalloproteinase 9 (MMP9) and the phosphorylation of dynamin-related protein 1 (DRP1). Notably, a significant increase in phosphorylated extracellular signal-regulated kinase (ERK), an upstream activator of MMP9 and DRP1, was observed. To investigate whether ERK activation was able to increase MMP9 protein levels and induce DRP1 phosphorylation, an ERK inhibitor was used, demonstrating that ERK-mediated MMP9 production and change in mitochondrial function was critical for the biological function of USP9X in prostate cancer cells. In conclusion, the present study demonstrated that USP9X is downregulated in prostate cancer and functions as an inhibitor of tumor cell invasion, possibly through the regulation of the ERK signaling pathway.

Deubiquitinase OTUD6A promotes proliferation of cancer cells via regulating Drp1 stability and mitochondrial fission

“…In support of this, our study has uncovered a novel regulatory pathway of Drp1 by deubiquitination and stability involving OTUD6A. In addition, USP9X is known to regulate the invasion of prostate cancer cells by inducing ERK-mediated Drp1 phosphorylation, but not the stability [45], suggesting that deubiquitinase may affect the phosphorylation of Drp1 and mitochondrial dynamics. However, in our study, the Drp1-S616A mutant had no effect on the binding of OTUD6A (Fig.…”

Protective Effects of Dexmedetomidine on the Vascular Endothelial Barrier Function by Inhibiting Mitochondrial Fission via ER/Mitochondria Contact

“…To further explore the mechanism of Dex regulating drp1 activation, a software package in vivo GPS (iGPS 1.0) (Wang et al, 2020) was used to predict the site-specific kinase for all phosphorylation-sites of Drp1. The prediction results showed that the extracellular regulated protein kinases1/2 (ERK1/2) could significantly regulate the Ser616 site of Drp1 ( Figure 5F and Table 1), and previous studies (Zhao et al, 2019;Zhang et al, 2019) also reported that ERK1/2 is an essential kinase that regulates Drp1. So the effect of ERK1/2 on Dex regulating (E) The intersections of F-actin and mitochondria of VECs in different groups were calculated by Image J software.…”

Crosstalk between Drp1 phosphorylation sites during mitochondrial remodeling and their impact on metabolic adaptation

“…However, these strategies fail to reflect the physiological regulation of Drp1 function, which is largely controlled by post-translational modifications, of which the phosphorylation at S600 and S579 have received the most attention. Although several reports have highlighted alterations in Drp1 phosphorylation levels in disease settings (Deus et al, 2020;Kashatus et al, 2015;Zhang et al, 2019), the impact, regulation, and interrelation between Drp1 S579 and S600 are poorly understood.…”