The lncRNA LENT interacts with DHX36 to regulate translation and suppress autophagy in melanoma.

The melanocyte lineage determining Microphthalmia-associated transcription factor (MITF) drives proliferation and survival of melanocytic melanoma cells through regulation of both coding genes and long non-coding RNAs (LncRNAs). Here we characterize LINC00520 (hereafter called LncRNA ENhancer of Translation, LENT) regulated by MITF and strongly expressed in melanocytic melanoma cells. LENT is essential for proliferation and survival of cultured melanocytic melanoma cells and xenograft tumours. LENT interacts with the G4 quadruplex resolvase DHX36 and both associate with the ribosome in the 80S and light polysome fractions. LENT modulates DHX36 association with a collection of mRNAs regulating their engagement in polysomes and their subsequent translation. These mRNAs encode proteins involved in endoplasmic reticulum (ER) and mitochondrial homeostasis as well as auto/mitophagy. Consequently, LENT silencing leads to extensive auto/mitophagy, compromised oxidative phosphorylation capacity and proteotoxic stress characterized by increased translation and mis-localization of mitochondrial proteins leading to apoptosis. The LENT-DHX36 axis therefore fine-tunes translation of proteins involved in ER and mitochondrial homeostasis to suppress auto/mitophagy and promote survival and proliferation of melanoma cells. Overall design: Melanoma cell-line 501M was sequenced in triplicates by RNA-seq (using either whole extract or 80S/Light/Heavy fractions) and RIP-seq (using either control IgG or DHX36 antibody) following si/shRNA silencing.