RNF146的SUMOylation导致Axin降解和激活Wnt/β-catenin信号通路，从而促进肝癌的进展。
SUMOylation of RNF146 results in Axin degradation and activation of Wnt/β-catenin signaling to promote the progression of hepatocellular carcinoma.
发表日期：2023 Apr 07
作者：
Wenjia Li, Qingfang Han, Yuanxin Zhu, Yingshi Zhou, Jingyuan Zhang, Weijun Wu, Yu Li, Long Liu, Yuntan Qiu, Kaishun Hu, Dong Yin
来源：
ONCOGENE
摘要：
异常的SUMO化促进了肝细胞癌（HCC）的发展，但其分子机制尚未得到很好的阐明。RING型E3泛素连接酶RNF146是Wnt/β-连环素信号通路的关键调节因子，在HCC中经常表现为高度活化。本研究发现，RNF146可以被SUMO3修饰。通过RNF146中所有溴氮基的突变，我们发现K19、K61、K174和K175是SUMO化的主要位点。UBC9/PIAS3/MMS21和SENP1/2/6分别介导SUMO3的结合与去掉结合。此外，RNF146的SUMO化促进其核定位，而去除SUMO化则将其定位于细胞质。重要的是，SUMO化促进了RNF146与Axin的相互作用，加速了Axin的泛素化和降解。有趣的是，只有UBC9/PIAS3和SENP1能作用于RNF146的K19/K175，并影响其在调节Axin稳定性方面的作用。另外，抑制RNF146的SUMO化可以抑制HCC的进展，不管是在体内还是在体外。患有RNF146和UBC9表达量较高的患者预后较差。总之，我们的结论是，RNF146在K19/K175的SUMO化促进了其与Axin的相互作用，并加速了Axin的降解，从而增强了β-连环素信号通路，促进了癌症进展。我们的发现揭示了RNF146 SUMO化是HCC的一个潜在治疗靶点。© 2023. 作者，独家授权给Springer Nature Limited.
Aberrant SUMOylation contributes to the progression of hepatocellular carcinoma (HCC), yet the molecular mechanisms have not been well elucidated. RING-type E3 ubiquitin ligase RNF146 is a key regulator of the Wnt/β-catenin signaling pathway, which is frequently hyperactivated in HCC. Here, it is identified that RNF146 can be modified by SUMO3. By mutating all lysines in RNF146, we found that K19, K61, K174 and K175 are the major sites for SUMOylation. UBC9/PIAS3/MMS21 and SENP1/2/6 mediated the conjugation and deconjugation of SUMO3, respectively. Furthermore, SUMOylation of RNF146 promoted its nuclear localization, while deSUMOylation induced its cytoplasmic localization. Importantly, SUMOylation promotes the association of RNF146 with Axin to accelerate the ubiquitination and degradation of Axin. Intriguingly, only UBC9/PIAS3 and SENP1 can act at K19/K175 in RNF146 and affect its role in regulating the stability of Axin. In addition, inhibiting RNF146 SUMOylation suppressed the progression of HCC both in vitro and in vivo. And, patients with higher expression of RNF146 and UBC9 have the worst prognosis. Taken together, we conclude that RNF146 SUMOylation at K19/K175 promotes its association with Axin and accelerates Axin degradation, thereby enhancing β-catenin signaling and contributing to cancer progression. Our findings reveal that RNF146 SUMOylation is a potential therapeutic target in HCC.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.