Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou 350122, China.
Anxi County Hospital, Quanzhou 362400, China.
Biochim Biophys Acta Mol Basis Dis. 2024 Jun;1870(5):167132. doi: 10.1016/j.bbadis.2024.167132. Epub 2024 Mar 31.
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.
EB 病毒（EBV）与多种癌症相关，包括 EBV 相关胃癌（EBVaGC）。本研究聚焦于 EBV 编码的 BALF1（BamH1 A 片段左读框 1），它是 EBV 相关癌症中关键的凋亡调控因子，但其在 EBVaGC 中的具体作用尚不清楚。我们的研究结果表明，BALF1 在胃癌细胞中的过表达显著增强了它们的增殖、迁移和对化疗诱导的凋亡的抵抗能力，证实了 BALF1 的致癌潜能。一个新的发现是 BALF1 通过泛素蛋白酶体途径发生降解。通过对 69 种去泛素化酶（DUB）的分析，卵巢肿瘤蛋白酶（OTU）结构域包含蛋白 1（OTUD1）被鉴定为维持 BALF1 蛋白稳定性的重要调控因子。此外，发现 BALF1 在调节 B 细胞淋巴瘤-2（Bcl-2）蛋白稳定性方面发挥作用，通过去泛素化增加其水平。该机制揭示了 BALF1 在胃癌中的多方面致癌作用，因为它直接和间接地促进了癌症的进展，特别是通过稳定具有抗凋亡特性的 Bcl-2。这些发现极大地加深了我们对 EBV 参与胃癌发病机制的理解。阐明 OTUD1 在 BALF1 调节中的作用及其对 Bcl-2 稳定化的影响，为 EBVaGC 的治疗干预提供了新的途径，弥合了病毒致癌和细胞蛋白调节之间的差距，并提供了一个更全面的观点，即 EBV 影响下胃癌的发展。
