LncRNA NRON promotes tumorigenesis by enhancing MDM2 activity toward tumor suppressor substrates

Abstract

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. image The E3 ligase MDM2 induces p53 degradation and promotes tumorigenesis. Here, the lncRNA NRON is found to regulate MDM2/MDMX heterodimerization and to enhance ubiquitin‐dependent degradation of multiple tumor suppressor proteins. NRON binds to MDM2 and MDMX and promotes their heterodimerization. NRON increases MDM2 E3 ligase activity toward p53, RB1, and other tumor suppressor substrates. NRON plays an oncogenic role in both p53 wild‐type and mutant cancer cells. High levels of NRON correlate with poor clinical outcome in breast cancer patients.