CUL3 (cullin 3)-mediated ubiquitination and degradation of BECN1 (beclin 1) inhibit autophagy and promote tumor progression
CUL3 (cullin 3)-mediated ubiquitination and degradation of BECN1 (beclin 1) inhibit autophagy and promote tumor progression
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CUL3 (cullin 3) 介导的 BECN1 (beclin 1) 泛素化和降解抑制自噬并促进肿瘤进展
DOI：
10.1080/15548627.2021.1912270
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发表时间：
2021-05-13
期刊：
影响因子：
13.3
通讯作者：
Zhu, Xiao-Feng
中科院分区：
文献类型：
--
作者：
Li, Xuan;Yang, Kai-Bin;Zhu, Xiao-Feng
巨噬/自噬在人类癌症的发展过程中起着重要的作用。BECN1 （beclin 1）是自噬调控的核心角色，在多种恶性肿瘤中下调。然而，其潜在的机制尚未完全阐明。在这里，我们发现CUL3 (cullin 3)，一个E3泛素连接酶，可以与BECN1相互作用并促进k48相关的泛素化和该蛋白的降解；此外，CUL3通过下调BECN1导致自噬活性降低。我们还发现KLHL38是cul3e3连接酶复合物介导的BECN1泛素化和降解的底物接头。在乳腺癌和卵巢癌中，CUL3能促进肿瘤细胞的增殖，CUL3的表达与患者预后不良有关。我们的研究揭示了BECN1泛素化和降解影响自噬活性并随后导致肿瘤进展的潜在机制，为调节自噬对抗癌症提供了一种新的治疗策略。
Macroautophagy/autophagy plays an important role during the development of human cancer. BECN1 (beclin 1), a core player in autophagy regulation, is downregulated in many kinds of malignancy. The underlying mechanism, however, has not been fully illuminated. Here, we found that CUL3 (cullin 3), an E3 ubiquitin ligase, could interact with BECN1 and promote the K48-linked ubiquitination and degradation of this protein; In addition, CUL3 led to a decrease in autophagic activity through downregulating BECN1. We also found that KLHL38 was a substrate adaptor of the CUL3 E3 ligase complex-mediated ubiquitination and degradation of BECN1. In breast and ovarian cancer, CUL3 could promote the proliferation of tumor cells, and the expression of CUL3 was related to poor prognosis in patients. Our study reveals the underlying mechanism of BECN1 ubiquitination and degradation that affects autophagic activity and subsequently leads to tumor progression, providing a novel therapeutic strategy that regulates autophagy to combat cancer.