TRAF6 inhibits colorectal cancer metastasis through regulating selective autophagic CTNNB1/β-catenin degradation and is targeted for GSK3B/GSK3β-mediated phosphorylation and degradation
TRAF6 inhibits colorectal cancer metastasis through regulating selective autophagic CTNNB1/β-catenin degradation and is targeted for GSK3B/GSK3β-mediated phosphorylation and degradation
复制标题
TRAF6 通过调节选择性自噬 CTNNB1/β-catenin 降解来抑制结直肠癌转移，并靶向 GSK3B/GSK3beta 介导的磷酸化和降解。
DOI：
10.1080/15548627.2019.1586250
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发表时间：
2019-09-02
期刊：
影响因子：
13.3
通讯作者：
Li, Jian-Ming
中科院分区：
文献类型：
--
作者：
Wu, Hua;Lu, Xing-Xing;Li, Jian-Ming
异常的 CTNNB1 信号传导是癌症，尤其是结直肠癌 (CRC) 的基本过程之一。在此，我们报道了 TRAF6（一种对炎症信号转导很重要的 E3 泛素连接酶）通过驱动选择性自噬 CTNNB1 降解机制来抑制上皮间质转化 (EMT) 和 CRC 转移。从机制上讲，TRAF6 通过其 LC3 相互作用区域“YxxL”与 MAP1LC3B/LC3B 相互作用，并催化 LC3B 的 K63 连接多泛素化。 LC3B 的 K63 连接泛素化促进了 LC3B-ATG7 复合物的形成，并且对于 LC3B 随后识别 CTNNB1 进行选择性自噬降解至关重要。然而，在大多数临床结直肠癌中，TRAF6 在 Thr266 位点被 GSK3B 磷酸化，从而触发 K48 连接的多泛素化和 TRAF6 的降解，从而减弱其对自噬依赖性 CTNNB1 信号传导的抑制活性。临床上，TRAF6 表达降低与 GSK3B 蛋白水平和活性升高以及 CRC 患者总生存期降低相关。药理抑制GSK3B活性可稳定TRAF6蛋白，促进CTNNB1降解，有效抑制EMT和CRC转移。因此，靶向TRAF6及其通路可能对治疗晚期结直肠癌有意义。
Aberrant CTNNB1 signaling is one of the fundamental processes in cancers, especially colorectal cancer (CRC). Here, we reported that TRAF6, an E3 ubiquitin ligase important for inflammatory signaling, inhibited epithelial-mesenchymal transition (EMT) and CRC metastasis through driving a selective autophagic CTNNB1 degradation machinery. Mechanistically, TRAF6 interacted with MAP1LC3B/LC3B through its LC3-interacting region 'YxxL' and catalyzed K63-linked polyubiquitination of LC3B. The K63-linked ubiquitination of LC3B promoted the formation of the LC3B-ATG7 complex and was critical to the subsequent recognition of CTNNB1 by LC3B for the selective autophagic degradation. However, TRAF6 was phosphorylated at Thr266 by GSK3B in most clinical CRC, which triggered K48-linked polyubiquitination and degradation of TRAF6 and thereby attenuated its inhibitory activity towards the autophagy-dependent CTNNB1 signaling. Clinically, decreased expression of TRAF6 was associated with elevated GSK3B protein levels and activity and reduced overall survival in CRC patients. Pharmacological inhibition of GSK3B activity stabilized the TRAF6 protein, promoted CTNNB1 degradation, and effectively suppressed EMT and CRC metastasis. Thus, targeting TRAF6 and its pathway may be meaningful for treating advanced CRC.