Work

A LINC00472-encoded polypeptide impedes migration and proliferation through modulation of the HDAC2/SP1 axis in non-small cell lung cancer cells

Year: 2025

Type: article

Abstract: While long non-coding RNAs (lncRNAs) are increasingly recognized as sources of functional micropeptides, their roles in non-small cell lung cancer (NSCLC) remain poorly characterized. This study investigates the therapeutic potential and molecular mechanism of LINC00472-encoded polypeptide in NSCLC. Through integration of ribosome profiling, transcriptomics, and co-expression analysis, we systematically identified lncRNA-encoded polypeptides in NSCLC. Translational competence was validated via ribosome affinity purification (TRAP), Western blot, and immunofluorescence (IF). Functional assays (CCK-8, EdU, wound healing, transwell) and xenograft models assessed anti-tumor effects. HDAC2/SP1 interaction dynamics were analyzed by co-IP and luciferase reporter systems. Multi-omics screening identified LINC00472 as a bifunctional transcript encoding a 15-aa polypeptide (LINC00472-ORF). LINC00472-ORF exhibited potent tumor-suppressive activity, reducing NSCLC proliferation and motility in vitro, while suppressing xenograft growth in vivo. Mechanistically, LINC00472-ORF disrupted HDAC2/SP1 interaction, inducing SP1 hyperacetylation, cytoplasmic retention, and transcriptional inactivation of downstream oncogenic genes. We unveil LINC00472-ORF as a dual-function therapeutic agent that targets the HDAC2/SP1 axis to inhibit NSCLC progression. A 15-aa tumor-suppressive polypeptide (LINC00472-ORF) was first identified via multi-omics screening. LINC00472-ORF suppresses tumor growth by inhibiting NSCLC proliferation and motility in vitro and xenograft growth in vivo. LINC00472-ORF disrupts HDAC2/SP1 interaction to block SP1 transcriptional activity through hyperacetylation. SP1 hyperacetylation represses downstream oncogene transcription to inhibit NSCLC progression.

Source: Cancer Cell International

DOI: 10.1186/s12935-025-03901-z