A potent CBP/p300-Snail interaction inhibitor suppresses tumor growth and metastasis in wild-type p53-expressing cancer
A potent CBP/p300-Snail interaction inhibitor suppresses tumor growth and metastasis in wild-type p53-expressing cancer
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一种有效的 CBP/p300-Snail 相互作用抑制剂可抑制表达野生型 p53 的癌症中的肿瘤生长和转移
DOI：
10.1126/sciadv.aaw8500
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发表时间：
2020-04-01
期刊：
影响因子：
13.6
通讯作者：
Wu, Zhao-Qiu
中科院分区：
文献类型：
--
作者：
Li, Hong-Mei;Bi, Yan-Ran;Wu, Zhao-Qiu
锌指转录因子蜗牛在许多人类癌症中异常激活，并与不良预后相关。因此，靶向蜗牛有望在癌症患者中发挥治疗效益。然而，蜗牛传统上被认为是“不可药物的”，并且没有有效的药物抑制剂被确定。在这里，我们发现了一个小分子化合物CYD19，它与进化上保守的蜗牛蛋白精氨酸-174口袋形成了高亲和力的相互作用。在侵袭性癌细胞中，CYD19与蜗牛结合，从而破坏蜗牛与creb结合蛋白(CBP)/p300的相互作用，从而损害CBP/p300介导的蜗牛乙酰化，然后通过泛素-蛋白酶体途径促进其降解。此外，CYD19恢复了蜗牛依赖的野生型p53的抑制，从而在体外和体内降低肿瘤的生长和存活。此外，CYD19逆转蜗牛介导的上皮-间质转化（EMT），并损害EMT相关的肿瘤侵袭和转移。我们的研究结果表明，CYD19药物靶向蜗牛可能对癌症患者产生有效的治疗作用。
The zinc finger transcription factor Snail is aberrantly activated in many human cancers and associated with poor prognosis. Therefore, targeting Snail is expected to exert therapeutic benefit in patients with cancer. However, Snail has traditionally been considered "undruggable," and no effective pharmacological inhibitors have been identified. Here, we found a small-molecule compound CYD19 that forms a high-affinity interaction with the evolutionarily conserved arginine-174 pocket of Snail protein. In aggressive cancer cells, CYD19 binds to Snail and thus disrupts Snail's interaction with CREB-binding protein (CBP)/p300, which consequently impairs CBP/p300-mediated Snail acetylation and then promotes its degradation through the ubiquitin-proteasome pathway. Moreover, CYD19 restores Snail-dependent repression of wild-type p53, thus reducing tumor growth and survival in vitro and in vivo. In addition, CYD19 reverses Snail-mediated epithelial-mesenchymal transition (EMT) and impairs EMT-associated tumor invasion and metastasis. Our findings demonstrate that pharmacologically targeting Snail by CYD19 may exert potent therapeutic effects in patients with cancer.