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The LKB1 tumor suppressor gene is frequently mutated and inactivated in non-small cell lung cancer (NSCLC). Loss of LKB1 promotes cancer progression and influences therapeutic responses in preclinical studies; however, specific targeted therapies for lung cancer with LKB1 inactivation are currently unavailable. Here, we have identified a long noncoding RNA (lncRNA) signature that is associated with the loss of LKB1 function. We discovered that LINC00473 is consistently the most highly induced gene in LKB7-inactivated human primary NSCLC samples and derived cell lines. Elevated LINC00473 expression correlated with poor prognosis, and sustained LINC00473 expression was required for the growth and survival of LKB1inactivated NSCLC cells. Mechanistically, LINC00473 was induced by LKB1 inactivation and subsequent cyclic AMP-responsive element-binding protein (CREB)/CREB-regulated transcription coactivator (CRTC) activation. We determined that LINC00473 is a nuclear lncRNA and interacts with NONO, a component of the cAMP signaling pathway, thereby facilitating CRTC/ CREB-mediated transcription. Collectively, our study demonstrates that LINC00473 expression potentially serves as a robust biomarker for tumor LKB1 functional status that can be integrated into clinical trials for patient selection and treatment evaluation, and implicates LINC00473 as a therapeutic target for LKB1-inactivated NSCLC., Introduction Lung cancer is the leading cause of cancer-related deaths (1). Approximately 80% of lung cancer cases are non-small cell lung carcinoma (NSCLC). Conventional cytotoxic therapeutics show limited effectiveness; but [...]

N.sup.6-methyladenosine (m.sup.6A) modification of mRNA is emerging as an important regulator of gene expression that affects different developmental and biological processes, and altered m.sup.6A homeostasis is linked to cancer.sup.1-5. m.sup.6A modification is catalysed by METTL3 and enriched in the 3' untranslated region of a large subset of mRNAs at sites close to the stop codon.sup.5. METTL3 can promote translation but the mechanism and relevance of this process remain unknown.sup.1. Here we show that METTL3 enhances translation only when tethered to reporter mRNA at sites close to the stop codon, supporting a mechanism of mRNA looping for ribosome recycling and translational control. Electron microscopy reveals the topology of individual polyribosomes with single METTL3 foci in close proximity to 5' cap-binding proteins. We identify a direct physical and functional interaction between METTL3 and the eukaryotic translation initiation factor 3 subunit h (eIF3h). METTL3 promotes translation of a large subset of oncogenic mRNAs--including bromodomain-containing protein 4--that is also m.sup.6A-modified in human primary lung tumours. The METTL3-eIF3h interaction is required for enhanced translation, formation of densely packed polyribosomes and oncogenic transformation. METTL3 depletion inhibits tumorigenicity and sensitizes lung cancer cells to BRD4 inhibition. These findings uncover a mechanism of translation control that is based on mRNA looping and identify METTL3-eIF3h as a potential therapeutic target for patients with cancer.METTL3, the enzyme responsible for m.sup.6A modification, influences translation by interacting with eIF3h to mediate looping between the regions near the stop codon and 5' cap of mRNA., Author(s): Junho Choe [sup.1] [sup.2] , Shuibin Lin [sup.1] [sup.2] [sup.3] , Wencai Zhang [sup.4] , Qi Liu [sup.1] [sup.2] , Longfei Wang [sup.2] , Julia Ramirez-Moya [sup.1] [sup.5] , [...]