LncRNA NRON promotes tumorigenesis by enhancing MDM2 activity toward tumor suppressor substrates.
The E3 ligase MDM2 promotes tumor growth and progression by inducing ubiquitin-mediated degradation of P53 and other tumor-suppressing proteins. Here, we identified an MDM2-interacting lncRNA NRON, which promotes tumor formation by suppressing both P53-dependent and independent pathways. NRON binds to MDM2 and MDMX (MDM4) via two different stem-loops, respectively, and ... induces their heterogenous dimerization, thereby enhancing the E3 ligase activity of MDM2 toward its tumor-suppressing substrates, including P53, RB1, and NFAT1. NRON knockdown dramatically inhibits tumor cell growth in vitro and in vivo. More importantly, NRON overexpression promotes oncogenic transformation by inducing anchorage-independent growth in vitro and facilitating tumor formation in immunocompromised mice. Clinically, NRON expression is significantly associated with poor clinical outcome in breast cancer patients. Together, our data uncover a pivotal role of lncRNA that induces malignant transformation of epithelial cells by inhibiting multiple tumor suppressor proteins.
Mesh Terms:
Animals, Carcinogenesis, Cell Line, Tumor, Cell Transformation, Neoplastic, Mice, Proto-Oncogene Proteins c-mdm2, RNA, Long Noncoding, Tumor Suppressor Protein p53, Ubiquitin-Protein Ligases, Ubiquitination
Animals, Carcinogenesis, Cell Line, Tumor, Cell Transformation, Neoplastic, Mice, Proto-Oncogene Proteins c-mdm2, RNA, Long Noncoding, Tumor Suppressor Protein p53, Ubiquitin-Protein Ligases, Ubiquitination
EMBO J
Date: Aug. 15, 2023
PubMed ID: 37382239
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