Actin remodeling confers BRAF inhibitor resistance to melanoma cells through YAP/TAZ activation
Actin remodeling confers BRAF inhibitor resistance to melanoma cells through YAP/TAZ activation
复制标题
DOI：
10.15252/embj.201592081
复制
发表时间：
2016-03-01
期刊：
影响因子：
11.4
通讯作者：
Kim, Joon
中科院分区：
文献类型：
--
作者：
Kim, Min Hwan;Kim, Jongshin;Kim, Joon
转录辅激活因子雅普及其辅因子TAZ的激活已显示促进对抗癌疗法的抗性。雅普/TAZ活性与肌动蛋白细胞骨架结构紧密耦合。然而，肌动蛋白重塑对癌症耐药性的影响仍然在很大程度上未被探索。在这里，我们报告了一个关键的作用，肌动蛋白重塑雅普/TAZ依赖的BRAF抑制剂耐药性BRAF V600 E突变黑色素瘤细胞。对BRAF抑制剂PLX 4032具有抗性的黑素瘤细胞表现出肌动蛋白应力纤维形成的增加，这似乎促进了雅普/TAZ的核积累。敲低雅普/TAZ降低了耐药黑色素瘤细胞的生存力，而组成型活性雅普的过表达诱导耐药性。此外，在黑色素瘤细胞中抑制肌动蛋白聚合和肌动球蛋白张力抑制了雅普/TAZ活化和PLX 4032抗性。我们的siRNA文库筛选鉴定肌动蛋白动力学调节剂TESK 1作为雅普/TAZ依赖性抗性途径的新的脆弱点。这些结果表明，抑制肌动蛋白重塑是抑制BRAF抑制剂治疗耐药性的潜在策略。
The activation of transcriptional coactivators YAP and its paralog TAZ has been shown to promote resistance to anti-cancer therapies. YAP/TAZ activity is tightly coupled to actin cytoskeleton architecture. However, the influence of actin remodeling on cancer drug resistance remains largely unexplored. Here, we report a pivotal role of actin remodeling in YAP/TAZ-dependent BRAF inhibitor resistance in BRAF V600E mutant melanoma cells. Melanoma cells resistant to the BRAF inhibitor PLX4032 exhibit an increase in actin stress fiber formation, which appears to promote the nuclear accumulation of YAP/TAZ. Knockdown of YAP/TAZ reduces the viability of resistant melanoma cells, whereas overexpression of constitutively active YAP induces resistance. Moreover, inhibition of actin polymerization and actomyosin tension in melanoma cells suppresses both YAP/TAZ activation and PLX4032 resistance. Our siRNA library screening identifies actin dynamics regulator TESK1 as a novel vulnerable point of the YAP/TAZ-dependent resistance pathway. These results suggest that inhibition of actin remodeling is a potential strategy to suppress resistance in BRAF inhibitor therapies.