Regulation of Histone Emulsification by HPDL via LDHA/LDHB Promotes EC Cell Proliferation

  • Oncol Res. 2026 Apr 22;34(5):31. doi: 10.32604/or.2026.068833.
Yan Wang  1 ,  Jialei Zhu  2 ,  Shiyang Wei  3  4 ,  Lijie Jin  1 ,  Zhanqiu Liu  1 ,  Jie Xu  1 ,  Nana Yang  1 ,  Xuefeng Jiang  4 ,  Caizhi Wang  1 ,  Lingling Wang  1
Affiliations
  • 1. Department of Obstetrics and Gynecology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, China.
  • 2. Department of Gynecology, Huaiyuan County Hospital of Traditional Chinese Medicine, Bengbu, China.
  • 3. Department of Gynecology, People's Hospital of Guangxi Zhuang Autonomous Region, Qingxiu District, Nanning, China.
  • 4. Department of Gynecology, The First Affiliated Hospital of Jinan University, Guangzhou, China.
PMID: 42065070 DOI: 10.32604/or.2026.068833
Abstract

Background: The role of 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL) in endometrial Cancer (EC) progression remains poorly understood, particularly its involvement in metabolic-epigenetic crosstalk via lactate-driven histone lactylation. This study aimed to investigate HPDL's mechanistic contribution to EC pathogenesis.

Methods: Stable HPDL-overexpressing and knockdown EC cell lines (HEC-1-B and AN3CA) were generated using lentiviral vectors. Functional assays (proliferation, migration, invasion), subcutaneous xenograft models in BALB/c nude mice, and molecular analyses were conducted. Lactate levels, Pan-lysine lactylation (pan-kla), histone H3K18 lactylation (H3K18la), and effects of sodium oxamate (lactate modulator) were assessed. Lactate Dehydrogenase A/Lactate Dehydrogenase B (LDHA/LDHB) knockdown, promoter activity assays, and chromatin immunoprecipitation (ChIP) were performed to evaluate H3K18la occupancy at LDHA/LDHB promoters.

Results: HPDL knockdown reduced intracellular lactate, Pan-Kla, and H3K18la levels, while overexpression elevated these markers. Sodium oxamate amplified lactate and lactylation in HPDL-overexpressing cells but suppressed histone lactylation independently of HPDL. LDHA/LDHB knockdown diminished lactylation, repressed HPDL expression, and inhibited promoter activity. ChIP revealed H3K18la enrichment at LDHA/LDHB promoters in HPDL-overexpressing cells and reduced occupancy in knockdown models. HPDL enhanced EC cell proliferation, migration, and invasion in vitro. In vivo, HPDL-overexpressing xenografts exhibited accelerated tumor growth and larger volumes compared to controls.

Conclusions: HPDL regulates histone lactylation via LDHA/LDHB and promotes the proliferation of EC cells.

Keywords
4-hydroxyphenylpyruvate dioxygenase-like protein; Endometrial cancer; cell proliferation; histone lactylation; lactate dehydrogenase A/B.
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