Scholarlink

Objective <p>Ovarian cancer (OC) pathogenesis involves metabolic and epigenetic alterations, yet the underlying mechanisms remain unclear. Here, we sought to investigate the role and regulatory mechanism of lactate dehydrogenase C4 (LDHC4) in OC progression.</p> Methods <p>Multi-omics approaches were employed, including analyses of The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) cohorts, tissue microarrays, molecular biology experiments, and in vivo mouse models. LDHC4 expression was modulated in OC cell lines (A2780 and ES-2) to assess its effects on proliferation, migration, invasion, and metastasis. Lactylproteomic profiling, cleavage under targets and tagmentation (CUT&amp;Tag), and chromatin analyses were conducted to explore epigenetic mechanisms. The functional role of the downstream glycolytic enzyme phosphoglycerate kinase 1 (PGK1) was examined using pharmacological inhibition. Molecular docking and xenograft models were used to evaluate the therapeutic potential of targeting H4K12lac (lactylation of histone H4 at lysine 12).</p> Results <p>LDHC4 was significantly overexpressed in OC tissues and associated with poor overall survival (OS) (hazard ratio [HR] = 4.017, 95% confidence interval [CI]: 2.308–6.989, <i>P</i> &lt; 0.0001). It promoted proliferation, migration, invasion, and metastasis in vitro and in vivo. LDHC4 overexpression increased global lactylation, notably upregulating H4K12lac, which was enriched at the <i>PGK1</i> promoter. Inhibition of PGK1 with CBR-470-1 (half-maximal inhibitory concentration [IC₅₀] = 14.56 µM) suppressed OC growth and metastasis. Importantly, Elbasvir, identified as a high-affinity H4K12lac inhibitor, significantly reduced tumor burden in mouse xenografts across multiple doses (10–20&#xa0;mg·kg⁻¹) and downregulated H4K12lac and Ki-67 expression.</p> Conclusion <p>We conclude that LDHC4 promotes OC progression via lactylation-mediated epigenetic upregulation of PGK1. Targeting this pathway through H4K12lac inhibitors such as Elbasvir thus emerges as a viable therapeutic approach for OC.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

LDHC4 promotes ovarian cancer progression through H4K12 lactylation to regulate PGK1 expression and modulate glycolysis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月7日

查看全文
  • Yingying Lin,
  • Yanping Xiao,
  • Lingqing Luo,
  • Lingjing Lin,
  • Zhi Lin,
  • Cheng Sun,
  • Zhaolei Cui

摘要

Objective

Ovarian cancer (OC) pathogenesis involves metabolic and epigenetic alterations, yet the underlying mechanisms remain unclear. Here, we sought to investigate the role and regulatory mechanism of lactate dehydrogenase C4 (LDHC4) in OC progression.

Methods

Multi-omics approaches were employed, including analyses of The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) cohorts, tissue microarrays, molecular biology experiments, and in vivo mouse models. LDHC4 expression was modulated in OC cell lines (A2780 and ES-2) to assess its effects on proliferation, migration, invasion, and metastasis. Lactylproteomic profiling, cleavage under targets and tagmentation (CUT&Tag), and chromatin analyses were conducted to explore epigenetic mechanisms. The functional role of the downstream glycolytic enzyme phosphoglycerate kinase 1 (PGK1) was examined using pharmacological inhibition. Molecular docking and xenograft models were used to evaluate the therapeutic potential of targeting H4K12lac (lactylation of histone H4 at lysine 12).

Results

LDHC4 was significantly overexpressed in OC tissues and associated with poor overall survival (OS) (hazard ratio [HR] = 4.017, 95% confidence interval [CI]: 2.308–6.989, P < 0.0001). It promoted proliferation, migration, invasion, and metastasis in vitro and in vivo. LDHC4 overexpression increased global lactylation, notably upregulating H4K12lac, which was enriched at the PGK1 promoter. Inhibition of PGK1 with CBR-470-1 (half-maximal inhibitory concentration [IC₅₀] = 14.56 µM) suppressed OC growth and metastasis. Importantly, Elbasvir, identified as a high-affinity H4K12lac inhibitor, significantly reduced tumor burden in mouse xenografts across multiple doses (10–20 mg·kg⁻¹) and downregulated H4K12lac and Ki-67 expression.

Conclusion

We conclude that LDHC4 promotes OC progression via lactylation-mediated epigenetic upregulation of PGK1. Targeting this pathway through H4K12lac inhibitors such as Elbasvir thus emerges as a viable therapeutic approach for OC.