Vitamin C-induced competitive binding of HIF-1α and p53 to ubiquitin E3 ligase CBL contributes to anti-breast cancer progression through p53 deacetylation.
Vitamin C-induced competitive binding of HIF-1α and p53 to ubiquitin E3 ligase CBL contributes to anti-breast cancer progression through p53 deacetylation.
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DOI：
10.1016/j.fct.2022.113321
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发表时间：
2022-08
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通讯作者：
Y. Xiong;Shi-Fen Xu;Beibei Fu;Wanyan Tang;M. Zaky;R. Tian;R. Yao;Shanfu Zhang;Qingting Zhao;Weiqi Nian;Xiaoyuan Lin;Haibo Wu
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作者：
Y. Xiong;Shi-Fen Xu;Beibei Fu;Wanyan Tang;M. Zaky;R. Tian;R. Yao;Shanfu Zhang;Qingting Zhao;Weiqi Nian;Xiaoyuan Lin;Haibo Wu
维生素C（VC），就其对肿瘤的有效性而言，在癌症治疗中有争议的历史。然而，VC的抗癌机制尚未完全了解。本文报道了VC通过抑制HIF-1α依赖的细胞增殖和促进p53依赖的细胞凋亡对肿瘤细胞和异种移植瘤模型的抗肿瘤作用。具体地说，VC调节HIF-1α和p53与它们共同的E3泛素连接酶CBL的竞争性结合，从而抑制肿瘤的发生。此外，VC处理激活SIRT 1，导致p53去乙酰化和CBL-p53复合物解离，这反过来又促进CBL募集HIF-1α以蛋白酶体依赖性方式进行泛素化。总之，我们的研究结果为探索VC在癌症治疗中的治疗用途提供了一个机械原理。
Vitamin C (VC), in regard to its effectiveness against tumors, has had a controversial history in cancer treatment. However, the anticancer mechanisms of VC are not fully understood. Here, we reported that VC exerted an anticancer effect on cancer cell and xenograft models via inhibiting HIF-1α-dependent cell proliferation and promoting p53-dependent cell apoptosis. To be specific, VC modulated the competitive binding of HIF-1α and p53 to their common E3 ubiquitin ligase CBL, thereby inhibiting tumorigenesis. Moreover, VC treatment activated SIRT1, resulting in p53 deacetylation and CBL-p53 complex dissociation, which in turn facilitated CBL recruitment of HIF-1α for ubiquitination in a proteasome-dependent manner. Altogether, our results provided a mechanistic rationale for exploring the therapeutic use of VC in cancer therapy.