Department of Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Jiangsu Key Laboratory of Marine Pharmaceutical Compound Screening, College of Pharmacy, Jiangsu Ocean University, Lianyungang, China.
Cell Death Dis. 2021 Mar 25;12(4):317. doi: 10.1038/s41419-021-03580-4.
RNASET2 (Ribonuclease T2) functions as a tumor suppressor in preventing ovarian tumorigenesis. However, the mechanisms underlying the regulation of RNASET2 protein are completely unknown. Here we identified the F-box protein FBXO6, a substrate recognition subunit of an SCF (Skp1-Cul1-F-box protein) complex, as the ubiquitin E3 ligase for RNASET2. We found that the interaction between FBXO6 and RNASET2 induced RNASET2 instability through the ubiquitin-mediated proteasome degradation pathway. FBXO6 promoted K48-dependent ubiquitination of RNASET2 via its FBA domain. Through analysis of the TCGA dataset, we found that FBXO6 was significantly increased in ovarian cancer tissues and the high expression of FBXO6 was related to the poor overall survival (OS) of ovarian cancer patients at advanced stages. An inverse correlation between the protein levels of FBXO6 and RNASET2 was observed in clinic ovarian cancer samples. Depletion of FBXO6 promoted ovarian cancer cells proliferation, migration, and invasion, which could be partially reversed by RNASET2 silencing. Thus, our data revealed a novel FBXO6-RNASET2 axis, which might contribute to the development of ovarian cancer. We propose that inhibition of FBXO6 might represent an effective therapeutic strategy for ovarian cancer treatment.
RNASET2（核糖核酸酶 T2）作为一种肿瘤抑制因子，可防止卵巢肿瘤的发生。然而，RNASET2 蛋白调控的机制尚完全不清楚。在这里，我们鉴定了 F-box 蛋白 FBXO6，一种 SCF（Skp1-Cul1-F-box 蛋白）复合物的底物识别亚基，为 RNASET2 的泛素 E3 连接酶。我们发现，FBXO6 与 RNASET2 的相互作用通过泛素介导致蛋白酶体降解途径诱导 RNASET2 的不稳定性。FBXO6 通过其 FBA 结构域促进 K48 依赖性 RNASET2 的泛素化。通过对 TCGA 数据集的分析，我们发现 FBXO6 在卵巢癌组织中显著增加，并且 FBXO6 的高表达与晚期卵巢癌患者的总体生存（OS）不良相关。在临床卵巢癌样本中观察到 FBXO6 和 RNASET2 的蛋白水平呈负相关。FBXO6 的耗竭促进了卵巢癌细胞的增殖、迁移和侵袭，这可部分被 RNASET2 的沉默所逆转。因此，我们的数据揭示了一个新的 FBXO6-RNASET2 轴，它可能有助于卵巢癌的发展。我们提出抑制 FBXO6 可能代表一种治疗卵巢癌的有效治疗策略。
