Central Laboratory, Huashan Hospital, Fudan University, Shanghai, China.
Department of Laboratory Medicine, Huashan Hospital, Fudan University, Shanghai, China.
FASEB J. 2024 Feb 29;38(4):e23475. doi: 10.1096/fj.202301755R.
Ankyrin-repeat proteins with a suppressor of cytokine signaling box (ASB) proteins belong to the E3 ubiquitin ligase family. 18 ASB members have been identified whose biological functions are mostly unexplored. Here, we discovered that ASB3 was essential for hepatocellular carcinoma (HCC) development and high ASB3 expression predicted poor clinical outcomes. ASB3 silencing induced HCC cell growth arrest and apoptosis in vitro and in vivo. Liver-specific deletion of Asb3 gene suppressed diethylnitrosamine (DEN)-induced liver cancer development. Mechanistically, ASB3 interacted with death receptor 5 (DR5), which promoted ubiquitination and degradation of DR5. We further showed that ASB3 knockdown stabilized DR5 and increased the sensitivity of liver cancer cells to the treatment of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in a DR5-dependent manner in cellular and in animal models. In summary, we demonstrated that ASB3 promoted ubiquitination and degradation of DR5 in HCC, suggesting the potential of targeting ASB3 to HCC treatment and overcome TRAIL resistance.
锚蛋白重复蛋白具有细胞因子信号抑制盒 (ASB) 蛋白，属于 E3 泛素连接酶家族。已经鉴定出 18 种 ASB 成员，但其生物学功能大多尚未被探索。在这里，我们发现 ASB3 对肝细胞癌 (HCC) 的发展至关重要，高表达 ASB3 预示着较差的临床结局。ASB3 沉默在体外和体内诱导 HCC 细胞生长停滞和凋亡。肝脏特异性敲除 Asb3 基因抑制二乙基亚硝胺 (DEN) 诱导的肝癌发展。从机制上讲，ASB3 与死亡受体 5 (DR5) 相互作用，促进 DR5 的泛素化和降解。我们进一步表明，ASB3 敲低稳定了 DR5，并在细胞和动物模型中以 DR5 依赖的方式增加了肝癌细胞对肿瘤坏死因子相关凋亡诱导配体 (TRAIL) 治疗的敏感性。总之，我们证明了 ASB3 在 HCC 中促进了 DR5 的泛素化和降解，这表明靶向 ASB3 治疗 HCC 并克服 TRAIL 耐药性的潜力。
