• BMB Reports
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• v.54 no.12
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• pp.608-613
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• 2021

Melanoma, the most serious type of skin cancer, exhibits a high risk of metastasis. Although chemotherapeutic treatment for metastatic melanoma improves disease outcome and patient survival, some patients exhibit resistance or toxicity to the drug treatment regime. OTUB1 is a deubiquitinating enzyme overexpressed in several cancers. In this study, we investigated the effects of inhibiting OTUB1 expression on melanoma-cell proliferation and viability and identified the underlying molecular mechanism of action of OTUB1. We did endogenous OTUB1 knockdown in melanoma cells using short interfering RNA, and assessed the resulting phenotypes via MTT assays, Western blotting, and cell-cycle analysis. We identified differentially expressed genes between OTUB1-knockdown cells and control cells using RNA sequencing and confirmed them via Western blotting and reverse transcription polymerase chain reaction. Furthermore, we investigated the involvement of apoptotic and cell survival signaling pathways upon OTUB1 depletion. OTUB1 depletion in melanoma cells decreased cell viability and caused simultaneous accumulation of cells in the sub-G1 phase, indicating an increase in the apoptotic-cell population. RNA sequencing of OTUB1-knockdown cells revealed an increase in the levels of the apoptosis-inducing protein TRAIL. Additionally, OTUB1-knockdown cells exhibited increased sensitivity to PLX4032, a BRAF inhibitor, implying that OTUB1 and BRAF act collectively in regulating apoptosis. Taken together, our findings show that OTUB1 induces apoptosis of melanoma cells in vitro, likely by upregulating TRAIL, and suggest that approaches targeting OTUB1 can be developed to provide novel therapeutic strategies for treating melanoma.

• Journal of Life Science
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• v.30 no.5
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• pp.483-490
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• 2020

The ubiquitin system uses ligases and deubiquitinases (DUBs) to regulate ubiquitin position on protein substrates and is involved in many biological processes which determine stability, activity, and interaction of the target substrate. DUBs are classified in six groups according to catalytic domain, namely ubiquitin-specific proteases (USPs); ubiquitin C-terminal hydrolases (UCHs); ovarian tumor proteases (OTUs); Machado Joseph Disease proteases (MJDs); motif interacting with Ub (MIU)-containing novel DUB family (MINDY); and Jab1/MPN/MOV34 metalloenzymes (JAMMs). Otubain 1 (OTUB1) is a DUB in the OTU family which possesses both canonical and non-canonical activity and can regulate multiple cellular signaling pathways. In this review, we describe the function of OTUB1 through regulation of its canonical and non-canonical activities in multiple specifically cancer-associated pathways. The canonical activity of OTUB1 inhibits protein ubiquitination by cleaving Lys48 linkages while its non-canonical activity prevents ubiquitin transfer onto target proteins through binding to E2-conjugating enzymes, resulting in the induction of protein deubiquitination. OTUB1 can therefore canonically and non-canonically promote tumor cell proliferation, invasion, and drug resistance through regulating FOXM1, ERα, KRAS, p53, and mTORC1. Moreover, clinical research has demonstrated that OTUB1 overexpresses with high metastasis in many tumor types including breast, ovarian, esophageal squamous, and glioma. Therefore, OTUB1 has been suggested as a diagnosis marker and potential therapeutic target for oncotherapy.