{
  "abstract": "Background SIRT6 acts as a tumour suppressor in multiple cancers by regulating glucose and lipid metabolism, but its role in intrahepatic cholangiocarcinoma (ICC) remains unclear.Objective We investigated the role and molecular mechanisms of SIRT6 in ICC development and progression.Design Spatial transcriptome and single-cell sequencing data from public ICC cohorts and clinical specimens were used to establish the clinical relevance of SIRT6 overexpression. B/R cell-established allografts and AKT/YAP-induced primary ICC mouse models were used to investigate the oncogenic role of SIRT6. The function of SIRT6 in metabolic regulation was assessed using seahorse analysis, metabolomics and isotope tracing. The transcriptional targets of SIRT6 were screened by RNA sequencing and confirmed by dual-luciferase assay and chromatin immunoprecipitation, and the molecular interactions and deacetylation activity of SIRT6 were analysed via co-immunoprecipitation.Results SIRT6 was highly expressed in both human and mouse ICC tissues and cell lines. SIRT6 knockdown significantly inhibited ICC cell growth in vitro and ICC development in mouse models. Hydrodynamic co-injection of SIRT6 and AKT resulted in ICC formation in mice. SIRT6 promoted glutamine synthesis by enhancing GLUL transcription and stabilising GLUL protein degradation. SIRT6 silencing decreased glutamine levels, subsequently reducing the levels of nucleotides and amino acids in ICC cells. Thus, SIRT6 or GLUL inhibitors can suppress ICC progression and significantly enhance the sensitivity to chemotherapy.Conclusions Our findings establish SIRT6 as an oncogenic driver in ICC by orchestrating glutamine metabolic reprogramming and highlight the SIRT6-GLUL axis as a potential therapeutic target for ICC.",
  "authors": [
    {
      "affiliations": [
        "School of Pharmacy, Huazhong University of Science and Technology, Tongji Medical College, Wuhan, Hubei, China"
      ],
      "name": "Mi Zhang"
    },
    {
      "affiliations": [
        "School of Pharmacy, Huazhong University of Science and Technology, Tongji Medical College, Wuhan, Hubei, China"
      ],
      "name": "Chanyuan Chen"
    },
    {
      "affiliations": [
        "School of Pharmacy, Huazhong University of Science and Technology, Tongji Medical College, Wuhan, Hubei, China"
      ],
      "name": "Haifeng Zhang"
    },
    {
      "affiliations": [
        "School of Pharmacy, Huazhong University of Science and Technology, Tongji Medical College, Wuhan, Hubei, China"
      ],
      "name": "Tanqing Long"
    },
    {
      "affiliations": [
        "Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, Henan, China"
      ],
      "name": "Tingjie Wang"
    },
    {
      "affiliations": [
        "School of Pharmacy, Huazhong University of Science and Technology, Tongji Medical College, Wuhan, Hubei, China"
      ],
      "name": "Nanjin Ding"
    },
    {
      "affiliations": [
        "School of Pharmacy, Huazhong University of Science and Technology, Tongji Medical College, Wuhan, Hubei, China"
      ],
      "name": "Ruitao Long"
    },
    {
      "affiliations": [
        "Department of Pharmacy, Huazhong University of Science and Technology, The Central Hospital of Wuhan, Wuhan, Hubei, China"
      ],
      "name": "Hua Wu"
    },
    {
      "affiliations": [
        "School of Pharmacy, Huazhong University of Science and Technology, Tongji Medical College, Wuhan, Hubei, China"
      ],
      "name": "Zhilu Ma"
    },
    {
      "affiliations": [
        "School of Pharmacy, Huazhong University of Science and Technology, Tongji Medical College, Wuhan, Hubei, China"
      ],
      "name": "Zhongyu Cheng"
    },
    {
      "affiliations": [
        "Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA"
      ],
      "name": "Junyan Tao"
    },
    {
      "affiliations": [
        "Department of Pathology, Huazhong University of Science and Technology, Tongji Hospital of Tongji Medical College, Wuhan, Hubei, China"
      ],
      "name": "Dong Kuang"
    },
    {
      "affiliations": [
        "School of Pharmacy, Huazhong University of Science and Technology, Tongji Medical College, Wuhan, Hubei, China"
      ],
      "name": "Lei Li"
    },
    {
      "affiliations": [
        "School of Pharmacy, Huazhong University of Science and Technology, Tongji Medical College, Wuhan, Hubei, China"
      ],
      "name": "Chuanrui Xu"
    }
  ],
  "title": "SIRT6 promotes intrahepatic cholangiocarcinoma development by reprogramming glutamine metabolism via enhanced GLUL",
  "uid": "bed3e08e-4ad2-557b-b4d6-dda3c65eefc5"
}