OTUD1 enhances gastric cancer aggressiveness by deubiquitinating EBV-encoded protein BALF1 to stabilize the apoptosis inhibitor Bcl-2

• Published in: Biochimica et biophysica acta. Molecular basis of disease Vol. 1870; no. 5; p. 167132
• Main Authors: Lin, Hanbin, Han, Yuting, Sang, Yuchao, Wu, Yuecheng, Tian, Mengyue, Chen, Xintan, Lin, Xu, Lin, Xinjian
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01-06-2024
• Subjects: BALF1; Bcl-2; Deubiquitinating enzyme; EBVaGC; OTUD1; Bcl-2; LMP1; CXCL8; MDBK; TRAF; ALS; mRNA; EBVaGC; ATCC; STR; OTU; Deubiquitinating enzyme; PI3K; FBS; BALF1; EBV; UPS; CCK-8; DUBs; SDS; LIC; siRNA; Co-IP; PVDF; LMP2A; BPLF1; ECL; SDS-PAGE; MAVS; Bcl2; IRF7; STING; BVDV; OTUD1; PCR; A20
• ISSN: 0925-4439; 1879-260X; 1879-260X
• DOI: 10.1016/j.bbadis.2024.167132

The Epstein-Barr virus (EBV) is implicated in several cancers, including EBV-associated gastric cancer (EBVaGC). This study focuses on EBV-encoded BALF1 (BamH1 A fragment leftward reading frame 1), a key apoptosis regulator in EBV-related cancers, whose specific impact on EBVaGC was previously unknown. Our findings indicate that BALF1 overexpression in gastric cancer cells significantly enhances their proliferation, migration, and resistance to chemotherapy-induced apoptosis, confirming BALF1's oncogenic potential. A novel discovery is that BALF1 undergoes degradation via the ubiquitin-proteasome pathway. Through analysis of 69 deubiquitinating enzymes (DUBs), ovarian tumor protease (OTU) domain-containing protein 1 (OTUD1) emerged as a vital regulator for maintaining BALF1 protein stability. Furthermore, BALF1 was found to play a role in regulating the stability of the B-cell lymphoma-2 (Bcl-2) protein, increasing its levels through deubiquitination. This mechanism reveals BALF1's multifaceted oncogenic role in gastric cancer, as it contributes both directly and indirectly to cancer progression, particularly by stabilizing Bcl-2, known for its anti-apoptotic characteristics. These insights significantly deepen our understanding of EBV's involvement in the pathogenesis of gastric cancer. The elucidation of OTUD1's role in BALF1 regulation and its influence on Bcl-2 stabilization provide new avenues for therapeutic intervention in EBVaGC, bridging the gap between viral oncogenesis and cellular protein regulation and offering a more holistic view of gastric cancer development under the influence of EBV.
•EBVaGC is regarded as the most prevalent malignant tumor triggered by EBV infection.•While EBV-encoded BALF1 is crucial in EBVaGC, its specific function remains unclear.•OTUD1 was identified as BALF1's key deubiquitinase via screening of a DUBs library.•BALF1 acts to deubiquitinate Bcl-2, leading to stabilization of its protein levels.•Increased apoptosis blocker Bcl-2 may explain EBVaGC's heightened aggressiveness.