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Hepatology International
Published in: Hepatology International 2/2023

Open Access 12-12-2022 | Metastasis | Original Article

HMGCL-induced β-hydroxybutyrate production attenuates hepatocellular carcinoma via DPP4-mediated ferroptosis susceptibility

Authors: Xiaohan Cui, Xiao Yun, Meiling Sun, Renzhi Li, Xiajie Lyu, Yuanxiang Lao, Xihu Qin, Wenbin Yu

Published in: Hepatology International | Issue 2/2023

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Abstract

Background

Metabolic disorder is an essential characteristic of tumor development. Ketogenesis is a heterogeneous factor in multiple cancers, but the effect of ketogenesis on hepatocellular carcinoma (HCC) is elusive.

Methods

We aimed to explain the role of ketogenesis-related hydroxy-methyl-glutaryl-CoA lyase (HMGCL) on HCC suppression. Expression pattern of HMGCL in HCC specimens was evaluated by immunohistochemistry (IHC). HMGCL was depleted or overexpressed in HCC cells to investigate the functions of HMGCL in vitro and in vivo. The anti-tumor function of HMGCL was studied in subcutaneous xenograft and Trp53Δhep/Δhep; c-Myc-driven HCC mouse models. The mechanism of HMGCL-mediated tumor suppression was studied by IHC, western blot (WB) and Cut & Tag.

Results

HMGCL depletion promoted HCC proliferation and metastasis, whereas its overexpression reversed this trend. As HMGCL catalyzes β-hydroxy-butyric acid (β-OHB) production, we discovered that HMGCL increased acetylation at histone H3K9, which further promoted the transcription of dipeptidyl peptidase 4 (DPP4), a key protein maintains intracellular lipid peroxidation and iron accumulation, leading to HCC cells vulnerability to erastin- and sorafenib-induced ferroptosis.

Conclusion

Our study identified a critical role of HMGCL on HCC suppression, of which HMGCL regulated H3K9 acetylation through β-OHB and modulating the expression of DPP4 in a dose-dependent manner, which led to ferroptosis in HCC cells.
Appendix
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Metadata
Title
HMGCL-induced β-hydroxybutyrate production attenuates hepatocellular carcinoma via DPP4-mediated ferroptosis susceptibility
Authors
Xiaohan Cui
Xiao Yun
Meiling Sun
Renzhi Li
Xiajie Lyu
Yuanxiang Lao
Xihu Qin
Wenbin Yu
Publication date
12-12-2022
Publisher
Springer India
Published in
Hepatology International / Issue 2/2023
Print ISSN: 1936-0533
Electronic ISSN: 1936-0541
DOI
https://doi.org/10.1007/s12072-022-10459-9

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