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Abstract：
Ubiquitination plays an essential role in protein stability, subcellular localization, and interactions. Crosstalk between different types of ubiquitination results in distinct biological outcomes for proteins. However, the role of ubiquitination-related crosstalk in lymph node (LN) metastasis and the key regulatory factors controlling this process have not been determined. Using high-throughput sequencing, we found that ubiquitin-conjugating enzyme E2 C (UBE2C) was overexpressed in bladder cancer (BCa) and was strongly associated with an unfavorable prognosis. Overexpression of UBE2C increased BCa lymphangiogenesis and promoted LN metastasis both in vitro and in vivo. Mechanistically, UBE2C mediated sodium-coupled neutral amino acid transporter 2 (SNAT2) monoubiquitination at lysine 59 to inhibit K63-linked polyubiquitination at lysine 33 of SNAT2. Crosstalk between monoubiquitination and K63-linked polyubiquitination increased SNAT2 membrane protein levels by suppressing epsin 1-mediated (EPN1-mediated) endocytosis. SNAT2 facilitated glutamine uptake and metabolism to promote VEGFC secretion, ultimately leading to lymphangiogenesis and LN metastasis in patients with BCa. Importantly, inhibition of UBE2C significantly attenuated BCa lymphangiogenesis in a patient-derived xenograft model. Our results reveal the mechanism by which UBE2C mediates crosstalk between the monoubiquitination and K63-linked polyubiquitination of SNAT2 to promote BCa metastasis and identify UBE2C as a promising target for treating LN-metastatic BCa.
摘要：
泛素化在蛋白质稳定性中起着至关重要的作用，亚细胞定位，和互动。不同类型的泛素化之间的串扰导致蛋白质的不同生物学结果。然而,泛素化相关串扰在淋巴结(LN)转移中的作用以及控制这一过程的关键调节因素尚未确定.采用高通量测序,我们发现,泛素结合酶E2C(UBE2C)在膀胱癌(BCa)中过度表达,并与不良预后密切相关.UBE2C的过表达在体外和体内都增加了BCa淋巴管生成并促进了LN转移。机械上,UBE2C介导的钠偶联中性氨基酸转运体2（SNAT2）在赖氨酸59处的单泛素化，以抑制在SNAT2的赖氨酸33处的K63连接的多泛素化。单泛素化和K63连接的聚泛素化之间的串扰通过抑制epsin1介导的（EPN1介导的）内吞作用增加了SNAT2膜蛋白水平。SNAT2促进谷氨酰胺的摄取和代谢，促进VEGFC的分泌，最终导致BCa患者的淋巴管生成和LN转移。重要的是,在患者来源的异种移植模型中,抑制UBE2C显著减弱BCa淋巴管生成。我们的结果揭示了UBE2C介导SNAT2的单泛素化和K63连接的多泛素化之间的串扰以促进BCa转移并将UBE2C鉴定为治疗LN转移性BCa的有希望的靶标的机制。
