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HMGB1/SET/HAT1 complex-mediated SASH1 repression drives glycolysis and metastasis in lung adenocarcinoma

Oncogene volume 42, pages 3407–3421 (2023)Cite this article

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Abstract

High-mobility group box 1 (HMGB1) can enhance the stability and accessibility of nucleus binding sites to nucleosomes and transcription factors. Recently, HMGB1 has been recognized as a positive regulator of tumor glutamine, and its overexpression has been correlated with tumorigenesis and cancer progression. However, functions and mechanisms of HMGB1 in regulation of glycolysis during cancer progression in lung adenocarcinoma (LUAD) is still unclear. Here, we found that intracellular HMGB1 was consistently upregulated in LUAD specimens, and positively relevant to tumor grade and poor survival. HMGB1 facilitated glycolysis and promoted metastasis through physical interaction with SET and HAT1, forming HMGB1/SET/HAT1 complex that inhibited H3K9 and H3K27 acetylation in LUAD. The functional proteins complex coordinated histone modification to suppress the expression of SASH1, thus further facilitating glycolysis and inducing the metastasis in vitro and in vivo. Consistent with this, the expression of SASH1 was negatively correlated with HMGB1, SET and GLUT1, and positively correlated with HAT1 in human LUAD specimens. Clinically, LUAD patients with high expression of HMGB1 and low expression of SASH1 exhibited the worst clinical outcomes. Overall, the findings of this study revealed the critical role of HMGB1 in glycolysis and metastasis by attenuating H3K9ace and H3K27ace through physical interacted with SET and HAT1, which may facilitate future targeted therapies.

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Fig. 1: HMGB1 facilitates glycolysis and correlates with poor prognosis in LUAD.
Fig. 2: Characterization of the HMGB1/SET/HAT1 complex.
Fig. 3: HMGB1/SET/HAT1 complex affects glycolysis by regulating H3K9ace and H3K27ace.
Fig. 4: HMGB1/SET/HAT1 acetylation complex transcriptional regulatory targets affects glycolysis.
Fig. 5: HMGB1/SET/HAT1 complex transcriptionally regulating SASH1 depends on the H3K9ace and H3K27ace mark.
Fig. 6: HMGB1/SET/HAT1 complex regulates glycolysis to promote metastasis of LUAD in vitro.
Fig. 7: HMGB1/SET/HAT1 complex regulates glycolysis to promote metastasis of LUAD in vivo.
Fig. 8: SASH1 expression is associated with HMGB1 expression in human LUAD specimens.

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Acknowledgements

We would like to acknowledge Tianjin Medical University Cancer Institute and Hospital for providing tissues from patients with NSCLC. We acknowledge TopEdit LLC for the linguistic editing and proofreading during the preparation of this manuscript. This work was supported by grants from the National Natural Science Foundation of China (Grant No. 81974246), Tianjin Key Medical Discipline (Specialty) Construction Project (TJYXZDXK-009A), Tianjin Natural Science Fund (No. 22JCYBJC01050) and Tianjin Research Innovation Project for Postgraduate Students (Grant No. 2021YJSB263).

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Author notes

  1. These authors contributed equally: Fan Kou, Lei Wu, Yu Zheng.

Authors and Affiliations

  1. Department of Immunology, Tianjin Medical University Cancer Institute & Hospital, Tianjin, China

    Fan Kou, Lei Wu, Yeran Yi, Zhenyu Ji, Ziqi Huang, Shiwei Guo & Lili Yang

  2. Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin, China

    Fan Kou, Lei Wu, Yu Zheng, Yeran Yi, Zhenyu Ji, Ziqi Huang, Shiwei Guo & Lili Yang

  3. Tianjin’s Clinical Research Center for Cancer, Tianjin, China

    Fan Kou, Lei Wu, Yu Zheng, Yeran Yi, Zhenyu Ji, Ziqi Huang, Shiwei Guo & Lili Yang

  4. Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China

    Fan Kou, Lei Wu, Yeran Yi, Zhenyu Ji, Ziqi Huang, Shiwei Guo & Lili Yang

  5. Department of Interventional Pulmonology, Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, China

    Fan Kou

  6. Cancer Center, Beijing Luhe Hospital, Capital Medical University, Beijing, China

    Lei Wu

  7. Department of Clinical Pharmacology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China

    Yu Zheng

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Contributions

FK, LW, and LY were responsible for designing the study. FK, LW, YZ, and ZJ conducted the research. FK and YY performed data analysis and wrote the manuscript. ZH and SG revised the manuscript.

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Correspondence to Lili Yang.

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Animal experiments were approved by the Animal Care Committee of Tianjin Medical University (No. 2021019).

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Kou, F., Wu, L., Zheng, Y. et al. HMGB1/SET/HAT1 complex-mediated SASH1 repression drives glycolysis and metastasis in lung adenocarcinoma. Oncogene 42, 3407–3421 (2023). https://doi.org/10.1038/s41388-023-02850-z

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