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Liver-specific SIRT1 knockout-induced hyperglycemia promotes spontaneous lung adenocarcinomas through HSF1-MDM2

Oncogene (2026) Cite this article

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Abstract

Epidemiological studies have indicated a strong link between metabolic disease and an elevated risk of cancer. However, it has not been directly replicated in animal models, nor has its specific underlying mechanism been clarified. From our previous research, liver-specific SIRT1 knockout (LKO) mice developed hyperglycemia within two months and developed fatty liver with whole-body insulin resistance around nine months of age. When the mice’s age extended to one year, they presented surprisingly higher lung tumor vulnerabilities in contrast to wild type as determined by macroscopic observation and histological examination. Interestingly, all lung tumors in these mice were classified as lung adenocarcinomas. Microarray analysis revealed elevated levels of MDM2, an oncoprotein, leading to the downregulation of its target genes such as p21 and GADD45. In vitro, the disruption of MDM2 leads to impaired cell cycle checkpoints and increased cell proliferation, which is accompanied by genomic instability, eventually causing full transformation in normal lung epithelia. In addition, the heat shock factor 1 (HSF1) transcription factor was found to regulate MDM2 directly and would decrease in the nucleus under high glucose conditions. Knockdown of HSF1 in the bronchial epithelial cell line (NL20) can increase MDM2 expression and cell proliferation. Human lung adenocarcinomas also displayed elevated MDM2 levels, with a correlation between MDM2 expression and lung cancer survival rates. Collectively, our findings suggest that liver-specific SIRT1 knockout-induced hyperglycemia promotes spontaneous lung adenocarcinomas through the HSF1-MDM2 pathway. Hyperglycemia may represent an underexplored cause of lung adenocarcinomas through impairment of cell cycle checkpoints, providing valuable insights for lung cancer prevention and future precision medicine.

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Fig. 1: SIRT1 LKO mice generated spontaneous lung adenocarcinomas.
The alternative text for this image may have been generated using AI.
Fig. 2: SIRT1 LKO mice lung tissues exhibit increased cancer-related pathways.
The alternative text for this image may have been generated using AI.
Fig. 3: In vitro, NL20 cells under high glucose carried genome instability and were enabled for full transformation.
The alternative text for this image may have been generated using AI.
Fig. 4: HSF1 regulates expression of MDM2 under glucose stimulation.
The alternative text for this image may have been generated using AI.
Fig. 5: Reducing HSF1 mimics the consequence caused by high glucose in NL20-Low cells.
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Fig. 6: SIRT1 LKO mice bearing hyperglycemia generate spontaneous lung adenocarcinomas through HSF1-MDM2.
The alternative text for this image may have been generated using AI.
Fig. 7
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Data availability

The data underlying this article will be shared on reasonable request to the corresponding author. The microarray datasets generated and analyzed during the current study are available in the NCBI BioProject repository under accession number GSE326924. Individual sample metadata can be accessed via BioSample numbers SAMN56537197–SAMN56537206.

References

  1. Gyamfi J, Kim J, Choi J. Cancer as a metabolic disorder. Int J Mol Sci. 2022;23:1155

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Siegel RL, Giaquinto AN, Jemal A. Cancer statistics, 2024. CA Cancer J Clin. 2024;74:12–49.

    PubMed  Google Scholar 

  3. Leiter A, Veluswamy RR, Wisnivesky JP. The global burden of lung cancer: current status and future trends. Nat Rev Clin Oncol. 2023;20:624–39.

    Article  PubMed  Google Scholar 

  4. LoPiccolo J, Gusev A, Christiani DC, Jänne PA. Lung cancer in patients who have never smoked - an emerging disease. Nat Rev Clin Oncol. 2024;21:121–46.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Papagiannakopoulos T, Bauer MR, Davidson SM, Heimann M, Subbaraj L, Bhutkar A, et al. Circadian rhythm disruption promotes lung tumorigenesis. Cell Metab. 2016;24:324–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Echouffo-Tcheugui JB, Perreault L, Ji L, Dagogo-Jack S. Diagnosis and management of prediabetes: a review. JAMA. 2023;329:1206–16.

    Article  PubMed  Google Scholar 

  7. Koo N, Sharma AK, Narayan S. Therapeutics targeting p53-MDM2 interaction to induce cancer cell death. Int J Mol Sci. 2022;23:5005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Wang W, Albadari N, Du Y, Fowler JF, Sang HT, Xian W, et al. MDM2 inhibitors for cancer therapy: the past, present, and future. Pharm Rev. 2024;76:414–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Wu QJ, Zhang TN, Chen HH, Yu XF, Lv JL, Liu YY, et al. The sirtuin family in health and disease. Signal Transduct Target Ther. 2022;7:402.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Majeed Y, Halabi N, Madani AY, Engelke R, Bhagwat AM, Abdesselem H, et al. SIRT1 promotes lipid metabolism and mitochondrial biogenesis in adipocytes and coordinates adipogenesis by targeting key enzymatic pathways. Sci Rep. 2021;11:8177.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Yang Y, Liu Y, Wang Y, Chao Y, Zhang J, Jia Y, et al. Regulation of SIRT1 and its roles in inflammation. Front Immunol. 2022;13:831168.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Alves-Fernandes DK, Jasiulionis MG. The role of SIRT1 on DNA damage response and epigenetic alterations in cancer. Int J Mol Sci. 2019;20:3153

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Wang RH, Kim HS, Xiao C, Xu X, Gavrilova O, Deng C-X. Hepatic Sirt1 deficiency in mice impairs mTorc2/Akt signaling and results in hyperglycemia, oxidative damage, and insulin resistance. J Clin Investig. 2011;121:4477.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Wang RH, Sengupta K, Li C, Kim HS, Cao L, Xiao C, et al. Impaired DNA damage response, genome instability, and tumorigenesis in SIRT1 mutant mice. Cancer cell. 2008;14:312–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wang RH, Kim HS, Xiao C, Xu X, Gavrilova O, Deng CX. Hepatic Sirt1 deficiency in mice impairs mTorc2/Akt signaling and results in hyperglycemia, oxidative damage, and insulin resistance. J Clin Invest. 2011;121:4477–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Rekhtman N, Ang DC, Sima CS, Travis WD, Moreira AL. Immunohistochemical algorithm for differentiation of lung adenocarcinoma and squamous cell carcinoma based on large series of whole-tissue sections with validation in small specimens. Mod Pathol. 2011;24:1348–59.

    Article  PubMed  Google Scholar 

  17. Hanahan D. Hallmarks of cancer: new dimensions. Cancer Discov. 2022;12:31–46.

    Article  CAS  PubMed  Google Scholar 

  18. Jones AN, Scheurlen KM, Macleod A, Simon HL, Galandiuk S. Obesity and inflammatory factors in the progression of early-onset colorectal cancer. Cancers. 2024;16:1403

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Khandekar MJ, Cohen P, Spiegelman BM. Molecular mechanisms of cancer development in obesity. Nat Rev Cancer. 2011;11:886–95.

    Article  CAS  PubMed  Google Scholar 

  20. Wu Y, Karapetyan E, Dutta P, Shaheen M, Vadgama JV. Inflammatory cytokines associated with obesity, type-2 diabetes, and hypertension exacerbate breast cancer risk in underserved African American and Latin American women. J Clin Med. 2024;13:1687

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Chang CJ, Freeman DJ, Wu H. PTEN regulates Mdm2 expression through the P1 promoter. J Biol Chem. 2004;279:29841–8.

    Article  CAS  PubMed  Google Scholar 

  22. Xiao X, Zuo X, Davis AA, McMillan DR, Curry BB, Richardson JA, et al. HSF1 is required for extra-embryonic development, postnatal growth and protection during inflammatory responses in mice. EMBO J. 1999;18:5943–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Moore MA, Park CB, Tsuda H. Implications of the hyperinsulinaemia-diabetes-cancer link for preventive efforts. Eur J Cancer Prev. 1998;7:89–107.

    CAS  PubMed  Google Scholar 

  24. Taubes G. Cancer research. Unraveling the obesity-cancer connection. Science. 2012;335:30–22.

    Article  Google Scholar 

  25. Vitale E, Rizzo A, Santa K, Jirillo E. Associations between “cancer risk”, “inflammation” and “metabolic syndrome”: a scoping review. Biology. 2024;13:352

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Cao Z, Zheng X, Yang H, Li S, Xu F, Yang X, et al. Association of obesity status and metabolic syndrome with site-specific cancers: a population-based cohort study. Br J Cancer. 2020;123:1336–44.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Chung GE, Yu SJ, Yoo JJ, Cho Y, Lee KN, Shin DW, et al. Differential risk of 23 site-specific incident cancers and cancer-related mortality among patients with metabolic dysfunction-associated fatty liver disease: a population-based cohort study with 9.7 million Korean subjects. Cancer Commun. 2023;43:863–76.

    Article  Google Scholar 

  28. Ramadori G, Konstantinidou G, Venkateswaran N, Biscotti T, Morlock L, Galié M, et al. Diet-induced unresolved ER stress hinders KRAS-driven lung tumorigenesis. Cell Metab. 2015;21:117–25.

    Article  CAS  PubMed  Google Scholar 

  29. Chen T, Lu L, Xu C, Lin X, Leung YK, Ho SM, et al. Inhibition role of atherogenic diet on ethyl carbamate induced lung tumorigenesis in C57BL/6J mice. Sci Rep. 2017;7:4723.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Shi D, Wu J, Wu Y, Lin X, Xu C, Lian X. High-fat diet-related obesity promotes urethane-induced lung tumorigenesis in C57BL/6J mice. Front Oncol. 2021;11:620993.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Lu C, Zhao H, Liu Y, Yang Z, Yao H, Liu T, et al. Novel role of the SIRT1 in endocrine and metabolic diseases. Int J Biol Sci. 2023;19:484–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Lam B, Nwadozi E, Haas TL, Birot O, Roudier E. High glucose treatment limits drosha protein expression and alters AngiomiR maturation in microvascular primary endothelial cells via an Mdm2-dependent mechanism. Cells. 2021;10:742

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lei CT, Tang H, Ye C, You CQ, Zhang J, Zhang CY, et al. MDM2 contributes to high glucose-induced glomerular mesangial cell proliferation and extracellular matrix accumulation via Notch1. Sci Rep. 2017;7:10393.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Li X, Sun X, Li L, Luo Y, Chi Y, Zheng G. MDM2-mediated ubiquitination of LKB1 contributes to the development of diabetic cataract. Exp Cell Res. 2022;417:113191.

    Article  CAS  PubMed  Google Scholar 

  35. Chin Y, Gumilar KE, Li XG, Tjokroprawiro BA, Lu CH, Lu J, et al. Targeting HSF1 for cancer treatment: mechanisms and inhibitor development. Theranostics. 2023;13:2281–300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Toma-Jonik A, Vydra N, Janus P, Widłak W. Interplay between HSF1 and p53 signaling pathways in cancer initiation and progression: non-oncogene and oncogene addiction. Cell Oncol. 2019;42:579–89.

    Article  Google Scholar 

  37. Swan CL, Sistonen L. Cellular stress response cross talk maintains protein and energy homeostasis. EMBO J. 2015;34:267–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Singleton KD, Wischmeyer PE. Glutamine induces heat shock protein expression via O-glycosylation and phosphorylation of HSF-1 and Sp1. JPEN J Parenter Enter Nutr. 2008;32:371–6.

    Article  CAS  Google Scholar 

  39. Wang X, Grammatikakis N, Siganou A, Calderwood SK. Regulation of molecular chaperone gene transcription involves the serine phosphorylation, 14-3-3 epsilon binding, and cytoplasmic sequestration of heat shock factor 1. Mol Cell Biol. 2003;23:6013–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Westerheide SD, Anckar J, Stevens SM Jr, Sistonen L, Morimoto RI. Stress-inducible regulation of heat shock factor 1 by the deacetylase SIRT1. Science. 2009;323:1063–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Gong J, Jing L. Glutamine induces heat shock protein 70 expression via O-GlcNAc modification and subsequent increased expression and transcriptional activity of heat shock factor-1. Minerva Anestesiol. 2011;77:488–95.

    CAS  PubMed  Google Scholar 

  42. Vujanac M, Fenaroli A, Zimarino V. Constitutive nuclear import and stress-regulated nucleocytoplasmic shuttling of mammalian heat-shock factor 1. Traffic. 2005;6:214–29.

    Article  CAS  PubMed  Google Scholar 

  43. Cho IY, Chang Y, Sung E, Park B, Kang JH, Shin H, et al. Glycemic status, insulin resistance, and mortality from lung cancer among individuals with and without diabetes. Cancer Metab. 2024;12:17.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Hua J, Lin H, Wang X, Qian ZM, Vaughn MG, Tabet M, et al. Associations of glycosylated hemoglobin, pre-diabetes, and type 2 diabetes with incident lung cancer: a large prospective cohort study. Diab Metab Syndr. 2024;18:102968.

    Article  CAS  Google Scholar 

  45. Sun W, Zhang X, Li N, He Y, Ji J, Zheng D. Genetic association of glycemic traits and antihyperglycemic agent target genes with the risk of lung cancer: a Mendelian randomization study. Diab Metab Syndr. 2024;18:103048.

    Article  CAS  Google Scholar 

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Acknowledgements

We thank all members of Ruihong Wang lab for helpful experimental support.

Funding

This work was supported by the following grants: Shaanxi Province of China (2024JC-YBQN-0243) to Yiwei Cao. Shaanxi Province of China (2023-JC-YB-671 and 2024JC- YBMS-731), “The Natural Science Foundation”-Boosting Project Plan of the Second Affiliated Hospital of Fourth Military Medical University (2021ZTXM-002), Clinical Research Program of Fourth Military Medical University (2023LC2325), Key R&D Project of Shaanxi Province Health Commission Scientific Research Innovation Capacity Enhancement Program(2025YF-20), Convergence Research Funding Initiative of Fourth Military Medical University (2024JC030) to Peng Yuan. Xi’an Jiaotong University Faculty Discovery and Innovation Initiative (xzy012025152) to Jiao Mu.

Author information

Author notes

  1. These authors contributed equally: Yiwei Cao, Jingyi Wei.

Authors and Affiliations

  1. Department of Exercise & Health Sciences, Xi’an Physical Education University, Xi’an, Shannxi, China

    Yiwei Cao & Bichan Xu

  2. Department of Nuclear Medicine, Tangdu Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China

    Jingyi Wei, Menghui Yuan & Peng Yuan

  3. Department of Oncology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China

    Jingyi Wei

  4. Cancer Center, Faculty of Health Sciences, University of Macau, Taipa, Macau SAR, China

    Qiang Chen

  5. MOE Frontiers Science Center for Precision Oncology, University of Macau, Taipa, Macau SAR, China

    Qiang Chen

  6. Surgery Branch, National Cancer Institute, Bethesda, MD, USA

    Haitao Wang & Ruihong Wang

  7. Department of Hematology, Xi’an Central Hospital, Xi’an, Shaanxi, China

    Jiao Mu

  8. Department of Interventional Radiology, Tangdu Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China

    Jiao Mu

  9. State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection (SRMP), Collaborative Innovation Center of Radiological Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou, China

    Shuhan Lu

  10. Anatomy Department, Faculty of Veterinary Medicine, Kafrelsheikh University, Kafrelsheikh, Egypt

    Mohammed A. El-Magd

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Contributions

Yiwei Cao: Conceptualization, investigation, data Curation, writing - original draft and visualization. Jingyi Wei: Investigation, data Curation, writing - original draft and visualization. Qiang Chen: Investigation, supervision and project administration. Haitao Wang: Software, formal analysis, validation, writing - review & editing, data Curation and visualization. Jiao Mu: Investigation and data Curation. Shuhan Lu: Investigation and data curation. Menghui Yuan: Supervision and resources. Mohammed A. El-Magd: Supervision and resources. Bichan Xu: Validation. Ruihong Wang: Conceptualization, methodology, writing - review & editing and supervision. Peng Yuan: Conceptualization, methodology, writing - review & editing and supervision. All authors discussed the results and implications and provided feedback on the manuscript at all stages.

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Correspondence to Peng Yuan.

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Cao, Y., Wei, J., Chen, Q. et al. Liver-specific SIRT1 knockout-induced hyperglycemia promotes spontaneous lung adenocarcinomas through HSF1-MDM2. Oncogene (2026). https://doi.org/10.1038/s41388-026-03826-5

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