P53 deficiency affects cholesterol esterification to exacerbate hepatocarcinogenesis.
Journal
Hepatology (Baltimore, Md.)
ISSN: 1527-3350
Titre abrégé: Hepatology
Pays: United States
ID NLM: 8302946
Informations de publication
Date de publication:
01 05 2023
01 05 2023
Historique:
received:
13
01
2022
accepted:
04
04
2022
medline:
20
4
2023
pubmed:
11
4
2022
entrez:
10
4
2022
Statut:
ppublish
Résumé
Cholesterol ester (CE) biosynthesis and homeostasis play critical roles in many cancers, including HCC, but their exact mechanistic contributions to HCC disease development require further study. Here, we report on a proposed role of tumor suppressor P53 in its repressing ubiquitin-specific peptidase 19 (USP19) and sterol O-acyltransferase (SOAT) 1, which maintains CE homeostasis. USP19 enhances cholesterol esterification and contributes to hepatocarcinogenesis (HCG) by deubiquitinating and stabilizing SOAT1. Loss of either SOAT1 or USP19 dramatically attenuates cholesterol esterification and HCG in P53-deficient mice fed with either a normal chow diet or a high-cholesterol, high-fat diet (HCHFD). SOAT1 inhibitor avasimibe has more inhibitory effect on HCC progression in HCHFD-maintained P53-deficient mice when compared to the inhibitors of de novo cholesterol synthesis. Consistent with our findings in the mouse model, the P53-USP19-SOAT1 signaling axis is also dysregulated in human HCCs. Collectively, our findings demonstrate that SOAT1 participates in HCG by increasing cholesterol esterification, thus indicating that SOAT1 is a potential biomarker and therapeutic target in P53-deficient HCC.
Sections du résumé
BACKGROUND AND AIMS
Cholesterol ester (CE) biosynthesis and homeostasis play critical roles in many cancers, including HCC, but their exact mechanistic contributions to HCC disease development require further study.
APPROACH AND RESULTS
Here, we report on a proposed role of tumor suppressor P53 in its repressing ubiquitin-specific peptidase 19 (USP19) and sterol O-acyltransferase (SOAT) 1, which maintains CE homeostasis. USP19 enhances cholesterol esterification and contributes to hepatocarcinogenesis (HCG) by deubiquitinating and stabilizing SOAT1. Loss of either SOAT1 or USP19 dramatically attenuates cholesterol esterification and HCG in P53-deficient mice fed with either a normal chow diet or a high-cholesterol, high-fat diet (HCHFD). SOAT1 inhibitor avasimibe has more inhibitory effect on HCC progression in HCHFD-maintained P53-deficient mice when compared to the inhibitors of de novo cholesterol synthesis. Consistent with our findings in the mouse model, the P53-USP19-SOAT1 signaling axis is also dysregulated in human HCCs.
CONCLUSIONS
Collectively, our findings demonstrate that SOAT1 participates in HCG by increasing cholesterol esterification, thus indicating that SOAT1 is a potential biomarker and therapeutic target in P53-deficient HCC.
Identifiants
pubmed: 35398929
pii: 01515467-202305000-00010
doi: 10.1002/hep.32518
doi:
Substances chimiques
Tumor Suppressor Protein p53
0
Cholesterol
97C5T2UQ7J
USP19 protein, human
EC 3.4.-
Endopeptidases
EC 3.4.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1499-1511Informations de copyright
Copyright © 2023 American Association for the Study of Liver Diseases.
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