TRIM11 facilitates chemoresistance in nasopharyngeal carcinoma by activating the β-catenin/ABCC9 axis via p62-selective autophagic degradation of Daple
TRIM11 facilitates chemoresistance in nasopharyngeal carcinoma by activating the β-catenin/ABCC9 axis via p62-selective autophagic degradation of Daple
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TRIM11 通过 Daple 的 p62 选择性自噬降解激活 β-catenin/ABCC9 轴，从而促进鼻咽癌的化疗耐药性
DOI：
10.1038/s41389-020-0229-9
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发表时间：
2020-05-07
期刊：
影响因子：
6.2
通讯作者：
Sang, Yi
中科院分区：
文献类型：
--
作者：
Zhang, Runa;Li, Si-Wei;Sang, Yi
化疗耐药是鼻咽癌治疗失败的主要原因。含三方基序蛋白（TRIM）家族成员在肿瘤发展和化疗失败中发挥重要作用。在这里，基于通过qRT-PCR对71个TRIM家族成员的筛选分析，我们首次证实了TRIM 11在耐药NPC细胞中的水平显著高于非耐药NPC细胞，并且高TRIM 11表达预测了较差的总生存期（OS）和无进展生存期（PFS）。N（6）-甲基腺苷（m6 A）在鼻咽癌耐药细胞中高度富集TRIM 11并增强其RNA稳定性。TRIM 11在体外可抑制细胞凋亡，在体内可促进顺铂（DDP）耐药，从而增强鼻咽癌的多药耐药。TRIM 11与Daple相关，并以p62选择性自噬方式促进Daple泛素介导的降解，进一步上调β-连环蛋白表达，通过直接结合ABCC 9启动子诱导ABCC 9表达。TRIM 11可能通过正向调节Daple/beta-catenin/ABCC 9信号通路来调节NPC耐药。因此，TRIM 11可能成为鼻咽癌化疗耐药的潜在诊断标志物和治疗靶点。
Chemotherapy resistance is the major cause of nasopharyngeal carcinoma (NPC) treatment failure. Tripartite motif-containing protein (TRIM) family members play important roles in tumor development and chemotherapy failure. Here, based on a screening analysis of 71 TRIM family members by qRT-PCR, we first confirmed that the TRIM11 levels were significantly higher in drug-resistant NPC cells than in non-drug-resistant NPC cells, and high TRIM11 expression predicted poor overall survival (OS) and progression-free survival (PFS). N(6)-Methyladenosine (m6A) was highly enriched in TRIM11 in NPC drug-resistant cells and enhanced its RNA stability. TRIM11 enhanced the multidrug resistance in NPC by inhibiting apoptosis in vitro and promoting cisplatin (DDP) resistance in vivo. TRIM11 associated with Daple and promoted Daple ubiquitin-mediated degradation in a p62-selective autophagic manner, further upregulating beta-catenin expression to induce ABCC9 expression by directly binding to the ABCC9 promoter. TRIM11 may regulate NPC drug resistance by positively modulating the Daple/beta-catenin/ABCC9 signaling pathway. Thus, TRIM11 may be a potential diagnostic marker and therapeutic target for chemoresistant NPC.