p53 suppresses lipid droplet–fueled tumorigenesis through phosphatidylcholine
Xiuduan Xu, … , Peng Li, Peng Jiang
Xiuduan Xu, … , Peng Li, Peng Jiang
Published January 9, 2024
Citation Information: J Clin Invest. 2024;134(4):e171788. https://doi.org/10.1172/JCI171788.
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Research Article Cell biology

p53 suppresses lipid droplet–fueled tumorigenesis through phosphatidylcholine

Abstract

Choline deficiency causes disorders including hepatic abnormalities and is associated with an increased risk of multiple types of cancer. Here, by choline-free diet–associated RNA-Seq analyses, we found that the tumor suppressor p53 drives the Kennedy pathway via PCYT1B to control the growth of lipid droplets (LDs) and their fueling role in tumorigenesis. Mechanistically, through upregulation of PCYT1B, p53 channeled depleted choline stores to phosphatidylcholine (PC) biosynthesis during choline starvation, thus preventing LD coalescence. Cells lacking p53 failed to complete this response to choline depletion, leading to hepatic steatosis and tumorigenesis, and these effects could be reversed by enforcement of PCYT1B expression or restoration of PC abundance. Furthermore, loss of p53 or defects in the Kennedy pathway increased surface localization of hormone-sensitive lipase on LDs to release specific fatty acids that fueled tumor cells in vivo and in vitro. Thus, p53 loss leads to dysregulation of choline metabolism and LD growth and couples perturbed LD homeostasis to tumorigenesis.

Authors

Xiuduan Xu, Jianqin Wang, Li Xu, Peng Li, Peng Jiang

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Figure 7

Suppression of PC biosynthesis by p53 loss increases surface localization of HSL to release specific fatty acids as fuel for tumorigenesis.

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Suppression of PC biosynthesis by p53 loss increases surface localizatio...
(A and C) Mice treated with shLacZ or shPCYT1B adenoviruses were maintained on a choline-deficient diet. (A) Fatty acid levels in the interstitial fluid of liver tissue. (C) Liver tissues and purified liver LDs were analyzed by Western blot, and isolated hepatocytes were immunostained as indicated. Scale bar: 10 μm. (B and D) p53+/+ and p53–/– mice were maintained on a choline-free diet with or without oral administration of 300 μL PC (10 mg/mL) daily. (B) Fatty acid levels in the interstitial fluid of liver tissue. (D) Liver tissue and purified liver LDs were analyzed by Western blot, and isolated hepatocytes were immunostained as indicated. Scale bar: 10 μm. (E) Levels of fatty acids in liver tissue interstitial fluid from p53+/+ and p53–/– mice maintained on a choline-free diet with or without oral administration of 100 μL HSL inhibitor (HSL-IN-1, 5 mg/mL) daily. (F–H) The experimental procedures are illustrated in Supplemental Figure 15E. (F) Representative images of liver tumor multiplicity and the number of tumors. (G) Liver tissues were analyzed by Western blot. (H) Representative histological analysis of H&E-stained tumors. n = 6 mice per group. Scale bar: 100 μm. (I and J) p53+/+ and p53–/– mice were maintained on a choline-free diet with or without oral administration of 100 μL HSL inhibitor (5 mg/mL) daily. The isolated hepatocytes were cultured in lipid-free medium, and the conditioned medium containing no oleate or 50 μM oleate was then used to culture HepG2 cells for different times. HepG2 cell proliferation and mTORC1 activity were determined. OA, oleic acid. Data are mean ± SD. Each experiment was carried out at least 3 independent times. P values were calculated by 2-tailed unpaired Student’s t test (F) or 2-way ANOVA (I). **P < 0.01, ***P < 0.001.