Updated project metadata. Long non-coding RNAs (lncRNAs) comprise a diverse class of gene expression regulators with emerging roles in many biological processes including cancer. Here we show that the expression of the lncRNA Hedgehog Interacting Protein Antisense 1 (HHIP-AS1) is a hallmark feature of human SHH-driven tumors. Importantly, loss of HHIP-AS1 leads to reduced tumor growth in SHH-driven tumors in vitro and in vivo. Our results demonstrate the power of cross-entity transcriptome-wide comparisons to identify novel epigenetic–regulatory lncRNA circuitries underlying human cancers.