Details

Autor(en) / Beteiligte

• Lin, Xiaorong
• Dinglin, Xiaoxiao
• Cao, Siting
• Zheng, Senyou
• Wu, Cheng
• Chen, Wenying
• Li, Qingjian
• Hu, Qian
• Zheng, Fang
• Wu, Zhiyong
• Lin, De-Chen
• Yao, Yandan
• Xu, Xiaoding
• Xie, Zhi
• Liu, Qiang
• Yao, Herui
• Hu, Hai

Titel

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

Ist Teil von

• Cell reports (Cambridge), 2020-06, Vol.31 (10), p.107753-107753, Article 107753

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2020

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. [Display omitted] •BDNF-AS induces tamoxifen resistance and malignant progression of breast cancers•BDNF-AS driven by MEF2A-regulated enhancer acts as scaffold of RNH1/TRIM21•BDNF-AS activates mTOR pathway by abolishing RNH1-regulated mTOR mRNA decay Epigenomic alterations can give rise to various tumor-promoting properties, including therapeutic resistance of cancer cells. Lin et al. show that the lncRNA BDNF-AS, driven by a MEF2A-regulated enhancer, activates the RNH1/TRIM21/mTOR cascade to induce endocrine resistance and malignant progression of breast cancer.