An integrative pan-cancer analysis of WWC family genes and functional validation in lung cancer.

The WW and C2 domain containing (WWC) protein family functions as scaffolds regulating cell proliferation and organ growth control through the Hippo signaling pathway. However, their pan-cancer dysregulation and mechanistic roles in signaling transduction have remained unclear. We performed integrated pan-cancer analyses of WWC family gene expression using data from The Cancer Genome Atlas (TCGA) across 33 different cancer types. Prognostic relevance was evaluated by survival analyses. WWC genetic alterations, DNA methylation, pathway activities, drug response, and tumor immunology were analyzed using online databases. Furthermore, we examined the functional roles of WWCs in lung cancer cells. We observed aberrant WWC expression in various cancers, which associated with patient prognosis. WWC hypermethylation occurred in many cancers and exhibited negative correlation with expression, alongside mutations linked to poor outcomes. Pathway analysis implicated WWCs as Hippo pathway scaffolds, while drug sensitivity analysis suggested associations with diverse chemotherapies. Additionally, pan-cancer analyses elucidated vital immunomodulatory roles for WWC through heterogeneous correlations with immune cell infiltrates, checkpoint molecules, tumor mutation burden, microsatellite instability, and chemokine pathways across cancers. Experimentally, WWCs suppressed lung cancer cell proliferation, migration, and invasion while enhancing apoptosis and paclitaxel chemosensitivity. Mechanistically, WWCs bound large tumor suppressor 1 and 2 (LATS1/2) kinases to stimulate phosphorylation cascades, thereby inhibiting nuclear translocation of the Yes-associated protein (YAP) oncoprotein. Taken together, our multi-omics characterization provides comprehensive evidence for WWCs as putative tumor suppressors across cancers via Hippo pathway modulation. WWCs may serve as prognostic markers and therapeutic targets in lung cancer.