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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 Article has an altmetric score of 5

p53 suppresses lipid droplet–fueled tumorigenesis through phosphatidylcholine

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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 5

PCYT1B is a metabolic tumor suppressor.

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PCYT1B is a metabolic tumor suppressor.
(A) Expression of PCYT1B in norm...
(A) Expression of PCYT1B in normal liver tissues and carcinoma of different stages was determined by immunohistochemistry (Human Protein Atlas; https://www.proteinatlas.org). Scale bar: 100 μm. (B) Kaplan-Meier survival curves of patients with liver cancer based on PCYT1B expression. Gray dotted lines indicate median survival time. (C–I) PCYT1B suppresses liver tumorigenesis in p53fl/fl;alb-cre mice. (C) Diagram depicting generation of liver tumor models. (D) Right: Representative expression of PCYT1B in tumors. Left: Representative images of liver tumor multiplicity and number of tumors. n = 8 (for PT3-GFP injection) or 10 (for PT3-PCYT1B injection) mice per group. (E) Kaplan-Meier survival curves of p53fl/fl;alb-cre mouse hydrodynamic tail vein injection (HTVI) with transposons expressing MYC and PCYT1B (GFP). n = 16 for GFP group; n = 17 for PCYT1B group. (F) Representative histological analysis of the tumors stained for H&E. Images and quantification were taken at tumor periphery. Scale bar: 100 μm. Levels of liver TG (G) and PC (H) were measured. Linear regression analysis was performed on mean LD size and tumor size (I) (n = 12). (J–O) p53fl/fl;alb-cre mice were fed a choline-free diet 6 weeks after injection with the indicated components using HTVI (J). (K) Representative images and number of liver tumors. (L) Liver tumor tissue PCYT1 activity. Absolute levels of PC (M) and TG (N) in the livers were measured. (O) Representative histological analysis of the tumors stained for H&E. n = 5 per group. Scale bar: 100 μm. All 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 (A, D, F, G, and H), 2-way ANOVA followed by Dunnett’s multiple-comparison test (K–N), linear regression analysis (I), or log-rank (Mantel-Cox) test (B and E). *P < 0.05, **P < 0.01, ****P < 0.0001.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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