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

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

  • Cancer Cell Int. 2025 Jul 16;25(1):263. doi: 10.1186/s12935-025-03901-z.
Lei Xu # 1,  Haoyong Kuang # 2,  Haodong Peng 2,  Sen Wu 1,  Yu Bai 3,  Xiangbo Jia 4,  Wenjian Yao 5
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan, 450003, China.
  • 2 Department of Thoracic Surgery, Zhengzhou University People's Hospital, Henan Provincial People's Hospital, Zhengzhou, Henan, 450003, China.
  • 3 Department of Pathology, Xinxiang Medical University, Xinxiang, Henan, 453003, China.
  • 4 Department of Thoracic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan, 450003, China. 651693151@qq.com.
  • 5 Department of Thoracic Surgery, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, Henan, 450003, China. doctor_yaowj@126.com.
  • # Contributed equally.
PMID: 40671075 DOI: 10.1186/s12935-025-03901-z
Abstract

Objective: 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.

Methods: 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.

Results: 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.

Conclusion: We unveil LINC00472-ORF as a dual-function therapeutic agent that targets the HDAC2/SP1 axis to inhibit NSCLC progression.

Keywords

Epigenetic-transcriptional regulation; HDAC2/SP1 axis; LINC00472; Multi-omics screening; NSCLC; lncRNA-encoded polypeptide.

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