Xiaorong Lin, Xiaoxiao Dinglin, Siting Cao, Senyou Zheng, Cheng Wu, Wenying Chen, Qingjian Li, Qian Hu, Fang Zheng, Zhiyong Wu, De-Chen Lin, Yandan Yao, Xiaoding Xu, Zhi Xie, Qiang Liu, Herui Yao, Hai Hu
Cell reports 2020 Jun 09Epigenomic 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. Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.
Xiaorong Lin, Xiaoxiao Dinglin, Siting Cao, Senyou Zheng, Cheng Wu, Wenying Chen, Qingjian Li, Qian Hu, Fang Zheng, Zhiyong Wu, De-Chen Lin, Yandan Yao, Xiaoding Xu, Zhi Xie, Qiang Liu, Herui Yao, Hai Hu. Enhancer-Driven lncRNA BDNF-AS Induces Endocrine Resistance and Malignant Progression of Breast Cancer through the RNH1/TRIM21/mTOR Cascade. Cell reports. 2020 Jun 09;31(10):107753
PMID: 32521278
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