p53-Intact Cancers Escape Tumor Suppression Through Loss of Long Noncoding RNA Dino

Many long noncoding RNA (lncRNA) genes are located near cancer-associated loci, suggesting potential roles in cancer development. However, conclusive evidence connecting the function of lncRNAs to the mechanism by which these genetic alterations impact cancer are largely lacking.  Here we report that DINO, the long noncoding RNA transcribed from the cancer-associated DINO/CDKN1A locus, suppresses tumor formation in a phenotype that does not require the protein encoded at the locus, p21. In rigorous, genetically-defined mouse models, Dino is a haplo-insufficient tumor suppressor of B cell lymphoma in which p21 does not suppress tumorigenesis. In human cancers, a discrete region of the DINO/CDKN1A locus is recurrently hypermethylated in human cancers, silencing DINO but not CDKN1A, the gene encoding p21. Hypermethylation silences DINO to impair the p53 signaling pathway in trans and is mutually exclusive with TP53 alterations, indicating that DINO and TP53 comprise a common tumor suppressor module. Therefore, DINO encodes a long noncoding RNA essential for tumor suppression that is recurrently silenced in human cancers as a mechanism to escape p53-dependent tumor suppression.