Zhao Andi, Zhou Chenyu, Li Jinjing, Wang Zijin, Zhu Hui, Shen Shiya, Shao Qing, Gong Qi, Liu Hu, Chen Xuejuan
Department of Ophthalmology, the First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China.
Nanjing Medical University, Nanjing 211166, China.
Acta Pharm Sin B. 2024 Dec;14(12):5201-5218. doi: 10.1016/j.apsb.2024.09.005. Epub 2024 Sep 13.
Uveal melanoma (UM) poses a significant lethality, with approximately 50% of those developing metastases surviving less than one year. In the progression of UM, vasculogenic mimicry (VM) induced by hypoxia plays a pivotal role, which also partially explains the resistance of UM to anti-angiogenic therapies. Nevertheless, the crucial molecular mechanisms underlying VM in the progression of UM remain unclear. We identified ubiquitin conjugating enzyme E2 G2 (UBE2G2) as a critical suppressor through transcriptomic sequencing and metastasis correlation screening. In UM, hypoxia-induced VM and metastasis are markedly exacerbated by UBE2G2 knockdown and significantly alleviated by its overexpression. Mechanistically, UBE2G2 directly binds to galectin 3 binding protein (LGALS3BP) and forms a complex with the E3 ubiquitin ligase tripartite motif containing 38 (TRIM38), facilitating ubiquitination-mediated degradation of LGALS3BP at the K104 residue. Furthermore, UBE2G2 inhibits oncogenic phenotypes by inactivating intracellular PI3K/AKT signaling and reprogramming the tumor microenvironment. Therefore, targeting intercellular and intracellular molecular mechanisms of the hypoxia-UBE2G2-LGALS3BP axis may contribute to developing various therapeutic strategies for UM.
葡萄膜黑色素瘤（UM）具有很高的致死率，发生转移的患者中约50%存活时间不到一年。在UM的进展过程中，缺氧诱导的血管生成拟态（VM）起关键作用，这也部分解释了UM对抗血管生成疗法的耐药性。然而，UM进展过程中VM的关键分子机制仍不清楚。我们通过转录组测序和转移相关性筛选，确定泛素结合酶E2 G2（UBE2G2）是一种关键抑制因子。在UM中，UBE2G2敲低显著加剧缺氧诱导的VM和转移，而其过表达则显著缓解。机制上，UBE2G2直接与半乳糖凝集素3结合蛋白（LGALS3BP）结合，并与含38个三联基序的E3泛素连接酶（TRIM38）形成复合物，促进LGALS3BP在K104残基处的泛素化介导降解。此外，UBE2G2通过使细胞内PI3K/AKT信号失活和重编程肿瘤微环境来抑制致癌表型。因此，针对缺氧-UBE2G2-LGALS3BP轴的细胞间和细胞内分子机制可能有助于开发针对UM的各种治疗策略。
