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

Abstract

Dynamin-related protein 1 (Drp1) is a cytosolic protein responsible for mitochondrial fission and is essential in the initiation and development of several human diseases, including cancer. However, the regulation of Drp1, especially of its ubiquitination, remains unclear. In this study, we report that the ovarian tumor-associated protease deubiquitinase 6A (OTUD6A) deubiquitylates and stabilizes Drp1, thereby facilitating regulation of mitochondrial morphology and tumorigenesis. OTUD6A is upregulated in human patients with colorectal cancer. Depletion of OTUD6A leads to lower Drp1 levels and suppressed mitochondrial fission and the affected cells are consequently less prone to tumorigenesis. Conversely, overexpression of OTUD6A increases Drp1 levels and its protein half-life and enhances cancer cell growth. Therefore, our results reveal a novel upstream protein of Drp1, and its role in tumorigenesis that is played, in part, through the activation of mitochondrial fission mediated by Drp1.

OTUD6A promotes prostate tumorigenesis via deubiquitinating Brg1 and AR

“…There is a relatively conserved loop, the Cys loop, which is responsible for the catalytic activation of OTUs. To investigate whether deubiquitinase activity is critical for OTUD6A functions in prostate cancer, we generated a catalytically inactive mutant of OTUD6A (OTUD6A C152A) 23 . We observed that reintroduction of wild-type (WT) but not the catalytically inactivated form of OTUD6A (C152A) reversed the reduced cell proliferation mediated by OTUD6A knockdown in PCa cells (Fig.…”

“…OTUD3 facilitates PTEN-related tumor suppressive responses and inhibits breast tumorigenesis, while in lung cancer, OTUD3 promotes tumorigenic phenotypes by stabilizing GRP78 53 , 54 . OTUD6A was reported to deubiquitinate and stabilize Drp1 and to regulate mitochondrial morphology in colon cancer 23 . In our study, we found that many OTU family members exhibited DNA amplification in PCa, while OTUD6A showed a specific and high amplification rate (15–20%), which emphasizes the potential roles of OTUD6A in the regulation of PCa.…”

“…Here, by mining diverse public PCa datasets, we found that many OTU family members showed high DNA copy number amplification, among which OTUD6A was the most frequently amplified. OTUD6A was previously reported to deubiquitinate and stabilize Drp1 to regulate mitochondrial morphology in colon cancer 23 . In this study, we report that OTUD6A can stabilize Brg1 and AR by removing Brg1 K27-linked polyubiquitination and AR K11-linked polyubiquitination, respectively, to promote PCa progression in vitro and in vivo, suggesting that targeting OTUD6A is a reasonable strategy for PCa therapy.…”

OTUD6A Is an Aurora Kinase A-Specific Deubiquitinase

“…There are only a limited number of studies on OTUD6A. However, it has been demonstrated that OTUD6A enhances the protein levels of one of the crucial EMT inducers, Snail [ 22 ], and promotes colorectal cancer by deubiquitinating and stabilizing DRP1 [ 23 ]. Therefore, the present study and the previous reports suggest that OTUD6A could be a feasible therapeutic target in human cancers.…”

“…The tumorigenic roles of OTUD6A have been demonstrated previously. OTUD6A enhances the protein levels of Snail, an EMT (epithelial-mesenchymal transition) inducer [ 22 ], and promotes tumorigenecity by deubiquitinating and stabilizing Drp1 [ 23 ]. We found that OTUD6A deubiquitinates Aurora-A to stabilize and activate by interacting through the kinase domain of Aurora-A.…”