2. Academic Validation
  3. ASH2L-K312-Lac Stimulates Angiogenesis in Tumors to Expedite the Malignant Progression of Hepatocellular Carcinoma

ASH2L-K312-Lac Stimulates Angiogenesis in Tumors to Expedite the Malignant Progression of Hepatocellular Carcinoma

  • Adv Sci (Weinh). 2025 Jul 29:e09477. doi: 10.1002/advs.202509477.
Hexu Han 1,  Shuai Wang 2,  Lixing Ma 3,  Haimeng Yin 4,  Xinxiang Cheng 5,  YiFan Wang 1,  Suqin Xia 1,  Yi Zhang 1,  Yue Zhang 2,  Rong Zhu 6,  Cuixia Liu 1,  Dakun Zhao 1,  Xiangqian Gu 6,  He Zhu 7,  Yin Yuan 8
Affiliations

Affiliations

  • 1 Department of Gastroenterology, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, Jiangsu, 225300, People's Republic of China.
  • 2 Clinical Medical Laboratory Center, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, Jiangsu, 225300, China.
  • 3 Department of Hepatobiliary Surgery, Changzhi People's Hospital, The Affiliated Hospital of Changzhi Medical College, No. 502 Changxing Middle Road, Changzhi, Shanxi, 046000, China.
  • 4 Department of Otorhinolaryngology Head and Neck surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong, 226001, China.
  • 5 Department of General Surgery of the Wuxi NO.2, Chinese Medcine Hospital, Wuxi, Jiangsu, 214000, China.
  • 6 Department of Hepatobiliary Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi People's Hospital, Wuxi Medical Center, Nanjing Medical University, Wuxi, 214000, China.
  • 7 Drug Clinical Trial Center, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, 225300, China.
  • 8 Department of Hepatobiliary Surgery, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou School of Clinical Medicine, Nanjing Medical University, Taizhou, Jiangsu, 225300, People's Republic of China.
PMID: 40726441 DOI: 10.1002/advs.202509477
Abstract

Hepatocellular carcinoma (HCC) is a common malignant tumor. However, the role of lactic acid-modified proteins in its pathogenesis is unclear. This study determines the distribution of a novel post-translational modification-protein lactylation-in HCC to identify potential targets and obtain mechanistic insights into this disease. Using high-throughput proteomics, lysine 312 lactylation (K312-lac) of the Set1/Ash2 Histone Methyltransferase complex subunit (ASH2L) is revealed as a candidate for further investigation. Subsequently, alanyl-tRNA synthetase 1 (AARS1) and histone deacetylase 1 (HDAC1) are shown to mediate lactylation modification of ASH2L. In vivo experiments demonstrate that ASH2L-K312-lac promotes HCC malignant progression and is positively correlated with tumor microvessel density, and vascular endothelial growth factor A (VEGFA) is identified as the key mediator in ASH2L-K312-lac-induced angiogenesis. High-throughput Sequencing reveals ASH2L-K312-lac enrichment in the genome regions encoding VEGFA, facilitating targeted recruitment of the mixed lineage leukemia complex to these loci and enhancing VEGFA expression through synergistic activation of enhancers and promoters. Finally, clinical sample analyses and robust in vivo preclinical experiments identify ASH2L-K312-lac as a promising therapeutic target for clinical application. These findings provide a theoretical foundation for the clinical translation of ASH2L-K312-lac-based treatment approaches, offering potential advancements in HCC diagnosis and treatment.

Keywords

ASH2L; H3K4me3; HCC; VEGFA; angiogenesis; lactylation.

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