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Author Spotlight: Investigating Liver Cancer Pathogenesis Using Patient-Derived Organoids
Published on: August 18, 2023
Targeting ER lipid raft-associated 1 reveals a coordinated cholesterol-dependent vulnerability in hepatocellular
Yiming Zhang1, Yushan Hou1, Xinxin Wang2
1State Key Laboratory of Medical Proteomics, National Center for Protein Sciences (Beijing), Research Unit of Proteomics Driven Cancer Precision Medicine (Chinese Academy of Medical Sciences), Beijing, China.
Background/Aims:
Dysregulated cholesterol metabolism is a hallmark of hepatocellular carcinoma (HCC) that drives tumor initiation and progression. However, clinical targeting of cholesterol metabolism has yielded limited benefits due to stringent feedback in tumor cells. Identifying a central mediator capable of restoring cholesterol homeostasis within the cell's intrinsically fine-tuned regulatory framework is urgently needed.
Methods:
We integrated a proteomic dataset from patients with cholesterol-dysregulated HCC into a global cholesterol metabolic regulatory network to identify potential therapeutic targets for disrupted cholesterol homeostasis. The prognostic significance of the candidate targets was further validated in an independent cohort through immunohistochemistry. Functional and mechanistic studies were conducted in vitro using HCC cell lines and in vivo using mouse models. The pharmacological efficacy of the candidate agent was evaluated in both subcutaneous and orthotopic HCC mouse models.
Results:
ER lipid raft-associated 1 (ERLIN1), a pivotal regulator of cholesterol metabolism reprogramming, was identified as an independent favorable prognostic indicator in HCC. ERLIN1 constrains HCC progression both in vitro and in vivo by stabilizing the INSIG1-SCAP-SREBP2 axis and maintaining the metabolic balance of intracellular cholesterol. Under hypoxia, impaired factor-inhibiting hypoxia-1-dependent hydroxylation of ASB11 at asparagine residues 90 and 92 enhances ASB11-mediated ERLIN1 degradation. Pharmacological targeting of this axis using zoledronic acid (ZoA) attenuated HCC progression by weakening the ASB11-ERLIN1 interaction and restoring cholesterol homeostasis.
Conclusions:
ERLIN1 represents a druggable metabolic vulnerability in cholesterol-dysregulated HCC. Targeting the ASB11-ERLIN1 axis with the clinically approved ZoA reestablishes cholesterol homeostasis and offers a promising therapeutic strategy to overcome the current limitations of cholesterol-targeted HCC therapies.
Insights
ERLIN1 stabilizes cholesterol balance in liver cancer, offering a new therapeutic target. Targeting the ASB11-ERLIN1 axis with zoledronic acid restores homeostasis and inhibits hepatocellular carcinoma (HCC) progression.
Area of Science:
- Biochemistry
- Oncology
- Metabolomics
Background:
- Cholesterol metabolism is crucial in hepatocellular carcinoma (HCC) development and progression.
- Current therapies targeting cholesterol metabolism in HCC are limited by cellular feedback mechanisms.
- A central mediator is needed to restore cholesterol homeostasis in HCC cells.
Purpose of the Study:
- To identify novel therapeutic targets for cholesterol-dysregulated HCC.
- To investigate the role of ERLIN1 in HCC progression and cholesterol homeostasis.
- To evaluate the efficacy of targeting the ASB11-ERLIN1 axis in HCC.
Main Methods:
- Integrated proteomic data with a global cholesterol metabolic network.
- Validated prognostic significance of targets via immunohistochemistry in an independent cohort.
- Conducted in vitro and in vivo functional studies in HCC cell lines and mouse models.
- Assessed pharmacological efficacy of zoledronic acid (ZoA) in HCC mouse models.
Main Results:
- ERLIN1 was identified as a favorable prognostic indicator in HCC, constraining tumor progression.
- ERLIN1 maintains intracellular cholesterol balance by stabilizing the INSIG1-SCAP-SREBP2 axis.
- Hypoxia impairs ERLIN1 stability via enhanced ASB11-mediated degradation.
- Zoledronic acid (ZoA) attenuated HCC progression by disrupting the ASB11-ERLIN1 interaction and restoring cholesterol homeostasis.
Conclusions:
- ERLIN1 is a druggable target representing a metabolic vulnerability in HCC.
- Targeting the ASB11-ERLIN1 axis with zoledronic acid reestablishes cholesterol homeostasis.
- This strategy offers a promising therapeutic approach for cholesterol-targeted HCC therapies.
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