Enhancer-Driven lncRNA BDNF-AS Induces Endocrine Resistance and Malignant Progression of Breast Cancer through the RNH1/TRIM21/mTOR Cascade.

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.