期刊
CELL REPORTS
卷 31, 期 10, 页码 -出版社
CELL PRESS
DOI: 10.1016/j.celrep.2020.107753
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资金
- National Science and Technology Major Project [2020ZX09201021]
- National Key Research and Development Program of China [2016YFC1302301]
- Natural Science Foundation of China [81672738, 81730077, U1601223]
- Guangzhou Science, Technology and Innovation Commission [201704020095, 201704020131]
- Guangdong Basic and Applied Basic Research Foundation [2019A1515110082]
- Guangdong Introducing Innovative and Entrepreneurial Teams [2016ZT06S252, 2016ZT06S638]
- Natural Science Foundation of Guangdong Province [2017A030313828]
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.
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