p53 promotes peroxisomal fatty acid β-oxidation to repress purine biosynthesis and mediate tumor suppression
p53 promotes peroxisomal fatty acid β-oxidation to repress purine biosynthesis and mediate tumor suppression
The metabolic pathways through which p53 functions as a potent tumor suppressor are incompletely understood. Here we report that, by associating with the Vitamin D receptor (VDR), p53 induces numerous genes encoding enzymes for peroxisomal fatty acid β-oxidation (FAO). This leads to increased cytosolic acetyl-CoA levels and acetylation of the enzyme 5-Aminoimidazole-4-Carboxamide Ribonucleotide Formyltransferase/IMP Cyclohydrolase (ATIC), which catalyzes the last two steps in the purine biosynthetic pathway. This acetylation step, mediated by lysine acetyltransferase 2B (KAT2B), occurs at ATIC Lys 266, dramatically inhibits ATIC activity, and inversely correlates with colorectal cancer (CRC) tumor growth in vitro and in vivo, and acetylation of ATIC is downregulated in human CRC samples. p53-deficient CRCs with high levels of ATIC is more susceptible to ATIC inhibition. Collectively, these findings link p53 to peroxisomal FAO, purine biosynthesis, and CRC pathogenesis in a manner that is regulated by the levels of ATIC acetylation.
Zhao, Jianhong
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Zhou, Xiaojun
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Lu, Mingzhu
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Wang, Genxin
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Tian, Chenhui
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Zhang, Jinmiao
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Chen, Zhiqiang
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Zhou, Xinyi
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Wu, Mingzhi
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Li, Mengjiao
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Li, Youjun
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Chen, Baoxiang
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Jiang, Congqing
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Elumalai, Nagarajan
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Tavassoli, Ali
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Liu, Yanliang
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Prochownik, Edward V.
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7 February 2023
Zhao, Jianhong
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Zhou, Xiaojun
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Lu, Mingzhu
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Wang, Genxin
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Tian, Chenhui
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Zhang, Jinmiao
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Chen, Zhiqiang
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Zhou, Xinyi
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Wu, Mingzhi
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Li, Mengjiao
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Li, Youjun
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Chen, Baoxiang
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Jiang, Congqing
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Elumalai, Nagarajan
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Tavassoli, Ali
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Liu, Yanliang
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Prochownik, Edward V.
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Zhao, Jianhong, Zhou, Xiaojun, Lu, Mingzhu, Wang, Genxin, Tian, Chenhui, Zhang, Jinmiao, Chen, Zhiqiang, Zhou, Xinyi, Wu, Mingzhi, Li, Mengjiao, Li, Youjun, Chen, Baoxiang, Jiang, Congqing, Elumalai, Nagarajan, Tavassoli, Ali, Liu, Yanliang and Prochownik, Edward V.
(2023)
p53 promotes peroxisomal fatty acid β-oxidation to repress purine biosynthesis and mediate tumor suppression.
Cell Death and Disease, 14 (2), [87].
(doi:10.1038/s41419-023-05625-2).
Abstract
The metabolic pathways through which p53 functions as a potent tumor suppressor are incompletely understood. Here we report that, by associating with the Vitamin D receptor (VDR), p53 induces numerous genes encoding enzymes for peroxisomal fatty acid β-oxidation (FAO). This leads to increased cytosolic acetyl-CoA levels and acetylation of the enzyme 5-Aminoimidazole-4-Carboxamide Ribonucleotide Formyltransferase/IMP Cyclohydrolase (ATIC), which catalyzes the last two steps in the purine biosynthetic pathway. This acetylation step, mediated by lysine acetyltransferase 2B (KAT2B), occurs at ATIC Lys 266, dramatically inhibits ATIC activity, and inversely correlates with colorectal cancer (CRC) tumor growth in vitro and in vivo, and acetylation of ATIC is downregulated in human CRC samples. p53-deficient CRCs with high levels of ATIC is more susceptible to ATIC inhibition. Collectively, these findings link p53 to peroxisomal FAO, purine biosynthesis, and CRC pathogenesis in a manner that is regulated by the levels of ATIC acetylation.
Text
s41419-023-05625-2 (3)
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Accepted/In Press date: 26 January 2023
Published date: 7 February 2023
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Funding Information:
The authors thank Professor Hong-Bing Shu and Bo Zhong (Wuhan University, Wuhan, China) for providing KATs plasmids and Trp53 mice, respectively. This work was supported by grants from the National Nature Science Foundation of China (32270828, 92057108, 81772609), the Fundamental Research Funds for the Central Universities (2042021kf0229), Sino-foreign Joint Scientific Research Platform Seed Fund of Wuhan University (WHUZZJJ202204), Engineering construction project of improving diagnosis and treatment ability of difficult diseases (Oncology, ZLYNXM202012) and Medical Science Advancement Program (Basic Medical Sciences) of Wuhan University (TFJC2018005). fl/fl
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© 2023, The Author(s).
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Local EPrints ID: 475996
URI: http://eprints.soton.ac.uk/id/eprint/475996
ISSN: 2041-4889
PURE UUID: 024ddb72-aa93-4c71-a54c-09081eaf1e70
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Date deposited: 03 Apr 2023 16:57
Last modified: 17 Mar 2024 03:07
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Contributors
Author:
Jianhong Zhao
Author:
Xiaojun Zhou
Author:
Mingzhu Lu
Author:
Genxin Wang
Author:
Chenhui Tian
Author:
Jinmiao Zhang
Author:
Zhiqiang Chen
Author:
Xinyi Zhou
Author:
Mingzhi Wu
Author:
Mengjiao Li
Author:
Youjun Li
Author:
Baoxiang Chen
Author:
Congqing Jiang
Author:
Yanliang Liu
Author:
Edward V. Prochownik
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