A Serum lncRNA Signature Determines Oncogenic YAP Activity in Cancer Patients

Biomarkers are typically identified by comparing human samples such as tissues and serum. However, reliable markers for transcriptionally active oncogenes remain elusive due to tumor heterogeneity and confounding signals from non-tumorous cells. We hypothesize that in vitro screening is sufficient to identify a long non-coding RNA (lncRNA) signature that is a specific marker for oncogenic transcriptional regulators. Exemplified for the Hippo pathway effectors, we integrated experimental NGS and cancer patient expression data with bioinformatics approaches to identify a yes-associated protein (YAP)-specific lncRNA signature in hepatocellular carcinoma (HCC) cells. The lncRNAs in this signature include CYTOR, MIR4435-2HG, SNHG1, and SNHG17, which partly promote HCC cell proliferation and control the sensitivity to YAP/TEA domain transcription factor (TEAD)-targeted inhibition. In HCC tissues, the lncRNA signature is associated with increased nuclear enrichment of YAP, the expression of YAP target genes, and poor clinical outcomes in patients. This association was also confirmed in cells and tissues of other malignancies, including lung adenocarcinoma (LUAD). Notably, the lncRNA signature is detectable in the serum of HCC patients and predicts YAP activation in tumor tissues. In summary, the Hippo pathway-associated lncRNA signature provides a readout for oncogenic YAP activity across cancers, suggesting its potential as a pan-cancer biomarker. Our results highlight oncogene-specific lncRNA signatures as valuable tools for diagnostics, therapy selection, and treatment monitoring.