2. Academic Validation
  3. CCNY-mediated phosphorylation and TET2-BACH1-driven DNA demethylation activate PRC1 to augment NSCLC progression

CCNY-mediated phosphorylation and TET2-BACH1-driven DNA demethylation activate PRC1 to augment NSCLC progression

  • J Exp Clin Cancer Res. 2025 Jul 15;44(1):206. doi: 10.1186/s13046-025-03472-x.
Dayu Huang # 1,  Xianglin Chu # 1,  Chunxiao Wu # 2,  Xuan Wang 1,  Mengkun Shi 1,  Xiaofeng Chen 1,  Yubao Lyu 3,  Dapeng Li 4,  Xuyu Gu 5
Affiliations

Affiliations

  • 1 Department of Thoracic Surgery, Huashan Hospital of Fudan University, Shanghai, 200040, P.R. China.
  • 2 Department of Thoracic Surgery, LongHua Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai, 200126, P.R. China.
  • 3 Department of Integrative Medicine, Huashan Hospital of Fudan University, Shanghai, 200040, P.R. China. 411245033@qq.com.
  • 4 Department of Oncology, The First Affiliated Hospital of Soochow University, Suzhou, 215006, Jiangsu, P.R. China. ldp802cn@163.com.
  • 5 Department of Oncology, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, China. guxuyu@126.com.
  • # Contributed equally.
PMID: 40665337 DOI: 10.1186/s13046-025-03472-x
Abstract

Background: The protein regulator of cytokinesis 1 (PRC1) is a prognostic marker characterized by low DNA methylation in lung Cancer. This study aims to examine the function of PRC1 in non-small cell lung Cancer (NSCLC) cells and investigates its regulatory mechanisms.

Methods: PRC1 expression in NSCLC cells was assessed using qPCR and western blot analyses. Loss- and gain-of-function assays of PRC1 were performed in NSCLC cells to analyze its effect on cell cycle progression and growth. Genetic knockdown or pharmaceutical inhibition of cyclin Y (CCNY), tet methylcytosine dioxygenase 2 (TET2), and BTB domain and CNC homolog 1 (BACH1) was conducted to analyze their influence on PRC1 phosphorylation or transcription. Subcutaneous xenograft and orthotopic isograft tumor models were generated for in vivo verification. Tissue microarray (TMA) and bioinformatics analyses were employed to evaluate the clinical prognostic value of CCNY, TET2, and PRC1 in NSCLC.

Results: PRC1 was highly expressed in NSCLC cells. Silencing either PRC1 or CCNY, which promotes PRC1 phosphorylation, substantially reduced cell growth in vitro, impaired spindle formation, promoted G2/M phase cell cycle arrest, increased multi-nucleated cells, and weakened tumorigenic activity of cells. Moreover, TET2 was found to induce DNA demethylation of PRC1 and activate its transcription by interacting with BACH1. Inhibition of TET2, BACH1, or the PLK1-PRC1 interaction weakened the tumorigenic potential of NSCLC cells in vivo. The TMA analysis revealed increased levels of CCNY, TET2, and phosphorylated PRC1 in tumor tissues. Bioinformatics analyses suggested that these molecules were correlated with unfavorable prognosis in NSCLC patients.

Conclusion: This study demonstrates a critical oncogenic role of PRC1 in NSCLC. CCNY, which modulates PRC1 phosphorylation, and the TET2-BACH1 cascade, which modulates demethylation and transcription of PRC1, may serve as promising targets for NSCLC management.

Keywords

BACH1; CCNY; DNA demethylation; NSCLC; PRC1; TET2.

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