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  3. ASH1L in Hepatoma Cells and Hepatic Stellate Cells Promotes Fibrosis-Associated Hepatocellular Carcinoma by Modulating Tumor-Associated Macrophages

ASH1L in Hepatoma Cells and Hepatic Stellate Cells Promotes Fibrosis-Associated Hepatocellular Carcinoma by Modulating Tumor-Associated Macrophages

  • Adv Sci (Weinh). 2024 Oct 8:e2404756. doi: 10.1002/advs.202404756.
Yuyang Du 1,  Shasha Wu 1,  Shaoyan Xi 2,  Wei Xu 3,  Liangzhan Sun 1 4 5,  Jingsong Yan 1,  Han Gao 1,  Yanchen Wang 6,  Jingyi Zheng 6,  Fenfen Wang 1,  Hui Yang 1,  Dan Xie 7,  Xi Chen 1,  Xijun Ou 8,  Xin-Yuan Guan 4 7 9,  Yan Li 6
Affiliations

Affiliations

  • 1 Department of Systems Biology, School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, China.
  • 2 Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, 510275, China.
  • 3 GMU-GIBH Joint School of Life Sciences, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Medical University, Guangzhou, 511436, China.
  • 4 Department of Clinical Oncology, The University of Hong Kong, Hong Kong, 999077, China.
  • 5 Institute of Cancer Research, Shenzhen Bay Laboratory, Shenzhen, 518067, China.
  • 6 Shenzhen Hospital, Southern Medical University, Shenzhen, 518000, China.
  • 7 State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, 510080, China.
  • 8 School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, China.
  • 9 The University of Hong Kong-Shenzhen Hospital, Shenzhen, 518053, China.
PMID: 39377228 DOI: 10.1002/advs.202404756
Abstract

Hepatocellular carcinoma (HCC) often occurs in the context of fibrosis or cirrhosis. Methylation of histone is an important epigenetic mechanism, but it is unclear whether histone methyltransferases are potent targets for fibrosis-associated HCC therapy. ASH1L, an H3K4 methyltransferase, is found at higher levels in activated hepatic stellate cells (HSCs) and hepatoma cells. To determine the role of ASH1L in vivo, transgenic mice with conditional Ash1l depletion in the hepatocyte cell lineage (Ash1lflox/floxAlbcre) or HSCs (Ash1lflox/floxGFAPcreERT2) are generated, and these mice are challenged in a diethylnitrosamine (DEN)/carbon tetrachloride (CCl4)-induced model of liver fibrosis and HCC. Depleting Ash1l in both hepatocytes and HSCs mitigates hepatic fibrosis and HCC development. Multicolor flow cytometry, bulk, and single-cell transcriptomic Sequencing reveal that ASH1L creates an immunosuppressive microenvironment. Mechanically, ASH1L-mediated H3K4me3 modification increases the expression of CCL2 and CSF1, which recruites and polarizes M2-like pro-tumorigenic macrophages. The M2-like macrophages further enhance tumor cell proliferation and suppress CD8+ T cell activation. AS-99, a small molecule inhibitor of ASH1L, demonstrates similar anti-fibrosis and tumor-suppressive effects. Of pathophysiological significance, the increased expression levels of mesenchymal ASH1L and M2 marker CD68 are associated with poor prognosis of HCC. The findings reveal ASH1L as a potential small-molecule therapeutic target against fibrosis-related HCC.

Keywords

ASH1L; fibrosis; hepatic stellate cells (HSCs); hepatocellular carcinoma (HCC); macrophage.

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