Department of Obstetrics and Gynecology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230031, China.
Department of Obstetrics and Gynecology, Bengbu Medical University, Bengbu, Anhui, 233030, China.
Oncogene. 2024 Jun;43(25):1885-1899. doi: 10.1038/s41388-024-03040-1. Epub 2024 Apr 25.
Receptor-interacting protein kinase 4 (RIPK4) is increasingly recognized as a pivotal player in ovarian cancer, promoting tumorigenesis and disease progression. Despite its significance, the posttranslational modifications dictating RIPK4 stability in ovarian cancer remain largely uncharted. In this study, we first established that RIPK4 levels are markedly higher in metastatic than in primary ovarian cancer tissues through single-cell sequencing. Subsequently, we identified UCHL3 as a key deubiquitinase that regulates RIPK4. We elucidate the mechanism that UCHL3 interacts with and deubiquitinates RIPK4 at the K469 site, removing the K48-linked ubiquitin chain and thus enhancing RIPK4 stabilization. Intriguingly, inhibition of UCHL3 activity using TCID leads to increased RIPK4 ubiquitination and degradation. Furthermore, we discovered that GSK3β-mediated phosphorylation of RIPK4 at Ser420 enhances its interaction with UCHL3, facilitating further deubiquitination and stabilization. Functionally, RIPK4 was found to drive the proliferation and metastasis of ovarian cancer in a UCHL3-dependent manner both in vitro and in vivo. Importantly, positive correlations between RIPK4 and UCHL3 protein expression levels were observed, with both serving as indicators of poor prognosis in ovarian cancer patients. Overall, this study uncovers a novel pathway wherein GSK3β-induced phosphorylation of RIPK4 strengthens its interaction with UCHL3, leading to increased deubiquitination and stabilization of RIPK4, thereby promoting ovarian cancer metastasis. These findings offer new insights into the molecular underpinnings of ovarian cancer and highlight potential therapeutic targets for enhancing antitumor efficacy.
受体相互作用蛋白激酶 4（RIPK4）在卵巢癌中越来越被认为是一个关键的参与者，促进肿瘤发生和疾病进展。尽管它具有重要意义，但决定卵巢癌中 RIPK4 稳定性的翻译后修饰在很大程度上仍未被探索。在这项研究中，我们首先通过单细胞测序确定 RIPK4 在转移性卵巢癌组织中的水平明显高于原发性卵巢癌组织。随后，我们确定 UCHL3 是一种关键的去泛素化酶，可调节 RIPK4。我们阐明了 UCHL3 与 RIPK4 在 K469 位点相互作用并去泛素化的机制，去除 K48 连接的泛素链，从而增强 RIPK4 的稳定性。有趣的是，使用 TCID 抑制 UCHL3 的活性会导致 RIPK4 泛素化和降解增加。此外，我们发现 GSK3β 介导的 RIPK4 丝氨酸 420 磷酸化增强了其与 UCHL3 的相互作用，促进进一步去泛素化和稳定。功能上，RIPK4 被发现以 UCHL3 依赖的方式在体外和体内驱动卵巢癌细胞的增殖和转移。重要的是，观察到 RIPK4 和 UCHL3 蛋白表达水平之间存在正相关，两者均作为卵巢癌患者预后不良的指标。总的来说，这项研究揭示了一个新的途径，即 GSK3β 诱导的 RIPK4 磷酸化增强了其与 UCHL3 的相互作用，导致 RIPK4 的去泛素化和稳定增加，从而促进卵巢癌的转移。这些发现为卵巢癌的分子基础提供了新的见解，并强调了增强抗肿瘤疗效的潜在治疗靶点。
