Pan-Cancer Analysis of Enhancer-Induced PAN3-AS1 and Experimental Validation as a WFDC13-Promoting Factor in Colon Cancer

Long non-coding RNAs (lncRNAs) act as epigenetic regulators for tumor hallmarks. This investigation sought to probe the carcinogenic trait of PAN3-AS1 across pan-cancer comprehensively.

We studied the diagnostic and prognostic features and the immune landscape of PAN3-AS1 across pan-cancer by bioinformatics approaches. The hierarchical regulatory networks governing PAN3-AS1 expression in colon cancer were explored via chromatin immunoprecipitation, luciferase activity assays, and RNA immunoprecipitation, etc. We screened drugs sensitive to WAP four-disulfide core domain 13 (WFDC13) by virtual screening and molecular docking.

Single-cell transcriptomics demonstrated that a variety of immune populations abnormally expressed PAN3-AS1 beyond tumor cells. Integration of data from multiple databases revealed that PAN3-AS1 was highly expressed and associated with a bad prognosis in various malignancies. Notably, PAN3-AS1 expression was correlated with a suppressive immune microenvironment. Moreover, we observed poor immunotherapy efficacy when PAN3-AS1 was highly expressed in melanoma. In vitro assays and functional enrichment analysis revealed that PAN3-AS1 was associated with cell proliferation and the immune response in colon cancer. Our experiments confirmed that PAN3-AS1 facilitated WFDC13 expression through competitive binding to hsa-miR-423-5p in colon cancer. Moreover, the present paper illustrated that enhancer activity exerts an important modulatory ability for PAN3-AS1 expression.

In short, PAN3-AS1 is a valuable biomarker for diagnosis and prognosis. PAN3-AS1 exhibits linkage to a cold tumor immune microenvironment (TME) and forecasts durable benefit from immunotherapy. Addressing the PAN3-AS1/miR-423-5p/WFDC13 axis might provide a novel option for improving immunotherapy efficacy in colon cancer.