Enhancer-Driven lncRNA BDNF-AS Induces Endocrine Resistance and Malignant Progression of Breast Cancer through the RNH1/TRIM21/mTOR Cascade
Enhancer-Driven lncRNA BDNF-AS Induces Endocrine Resistance and Malignant Progression of Breast Cancer through the RNH1/TRIM21/mTOR Cascade
复制标题
增强子驱动的lncRNA BDNF-AS通过RNH1/TRIM21/mTOR级联诱导乳腺癌内分泌抵抗和恶性进展
DOI：
10.1016/j.celrep.2020.107753
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发表时间：
2020-06-09
期刊：
影响因子：
8.8
通讯作者：
Hu, Hai
中科院分区：
文献类型：
--
作者：
Lin, Xiaorong;Dinglin, Xiaoxiao;Hu, Hai
表观基因组改变可以引起各种肿瘤促进特性，包括癌细胞的治疗抗性。在这里，我们确定了一种lncRNA，BDNF-AS，其过表达是由内分泌抵抗和三阴性乳腺癌（TNBC）中的MEF 2A调节增强子特异性驱动的。乳腺癌组织中高水平的BDNF-AS不仅表现为激素受体（HR）阳性患者的内分泌抵抗，而且与HR阳性和TNBC患者的不良结局相关。在机制上，BDNF-AS作为分子支架通过TRIM 21介导的RNH 1在K225处的泛素化来促进RNH 1蛋白降解。随后，BDNF-AS消除了RNH 1调节和RISC介导的mTOR mRNA衰减，因此维持了mTOR信号的激活。重要的是，mTOR抑制剂，而不是PI 3 K抑制剂，可以逆转由BDNF-AS过表达诱导的他莫昔芬耐药性。这些结果指向增强子激活的BDNF-AS/RNH 1/TRIM 21/mTOR级联在乳腺癌的内分泌抵抗和恶性进展中的主要调节作用。
Epigenomic alterations can give rise to various tumor-promoting properties, including therapeutic resistance of cancer cells. Here, we identify an lncRNA, BDNF-AS, whose overexpression is specifically driven by a MEF2A-regulated enhancer in endocrine-resistant and triple-negative breast cancer (TNBC). High levels of BDNF-AS in breast cancer tissues not only feature endocrine resistance in hormone receptor (HR)-positive patients but also correlate with poor outcomes in both HR-positive and TNBC patients. Mechanistically, BDNF-AS acts as a molecular scaffold to promote RNH1 protein degradation via TRIM21-mediated ubiquitination of RNH1 at K225. Subsequently, BDNF-AS abolishes RNH1-regulated and RISC-mediated mTOR mRNA decay, therefore sustaining the activation of mTOR signaling. Importantly, mTOR inhibitor, but not PI3K inhibitor, could reverse tamoxifen resistance induced by the overexpression of BDNF-AS. These results point toward a master regulatory role of an enhancer-activated cascade of BDNF-AS/RNH1/TRIM21/mTOR in endocrine resistance and malignant progression of breast cancer.