P53 deficiency affects cholesterol esterification to exacerbate hepatocarcinogenesis

Area of Science:

• Oncology
• Biochemistry
• Molecular Biology

Background:

• Cholesterol ester (CE) biosynthesis is crucial in cancers like hepatocellular carcinoma (HCC).
• The precise role of CE homeostasis in HCC development needs further elucidation.

Purpose of the Study:

• To investigate the role of tumor suppressor P53 in regulating CE homeostasis via USP19 and SOAT1.
• To explore the therapeutic potential of targeting the P53-USP19-SOAT1 axis in HCC.

Main Methods:

• Studied the P53-USP19-SOAT1 signaling axis in P53-deficient mouse models and human HCC samples.
• Administered SOAT1 inhibitor avasimibe and de novo cholesterol synthesis inhibitors.
• Utilized normal chow and high-cholesterol, high-fat diets (HCHFD).

Main Results:

• P53 represses USP19 and SOAT1, key regulators of CE homeostasis.
• USP19 stabilizes SOAT1, enhancing cholesterol esterification and promoting hepatocarcinogenesis (HCG).
• Loss of SOAT1 or USP19 attenuated CE and HCG in P53-deficient mice.
• Avasimibe showed greater efficacy than de novo synthesis inhibitors in HCHFD-fed P53-deficient mice.
• The P53-USP19-SOAT1 axis is dysregulated in human HCC.

Conclusions:

• SOAT1 promotes HCG by increasing cholesterol esterification.
• SOAT1 is a potential biomarker and therapeutic target for P53-deficient HCC.