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Nuclear VCP drives colorectal cancer progression by promoting fatty acid oxidation.

ABSTRACT: Fatty acid oxidation (FAO) fuels many cancers. However, knowledge of pathways that drive FAO in cancer remains unclear. Here, we revealed that valosin-containing protein (VCP) upregulates FAO to promote colorectal cancer growth. Mechanistically, nuclear VCP binds to histone deacetylase 1 (HDAC1) and facilitates its degradation, thus promoting the transcription of FAO genes, including the rate-limiting enzyme carnitine palmitoyltransferase 1A (CPT1A). FAO is an alternative fuel for cancer cells in environments exhibiting limited glucose availability. We observed that a VCP inhibitor blocked the upregulation of FAO activity and CPT1A expression triggered by metformin in colorectal cancer (CRC) cells. Combined VCP inhibitor and metformin prove more effective than either agent alone in culture and in vivo. Our study illustrates the molecular mechanism underlying the regulation of FAO by nuclear VCP and demonstrates the potential therapeutic utility of VCP inhibitor and metformin combination treatment for colorectal cancer.

SUBMITTER: Huang Y

PROVIDER: S-EPMC10576098 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Nuclear VCP drives colorectal cancer progression by promoting fatty acid oxidation.

Huang Youwei Y Wang Fang F Lin Xi X Li Qing Q Lu Yuli Y Zhang Jiayu J Shen Xi X Tan Jingyi J Qin Zixi Z Chen Jiahong J Chen Xueqin X Pan Guopeng G Wang Xiangyu X Zeng Yuequan Y Yang Shangqi S Liu Jun J Xing Fan F Li Kai K Zhang Haipeng H

Proceedings of the National Academy of Sciences of the United States of America 20231003 41

Fatty acid oxidation (FAO) fuels many cancers. However, knowledge of pathways that drive FAO in cancer remains unclear. Here, we revealed that valosin-containing protein (VCP) upregulates FAO to promote colorectal cancer growth. Mechanistically, nuclear VCP binds to histone deacetylase 1 (HDAC1) and facilitates its degradation, thus promoting the transcription of FAO genes, including the rate-limiting enzyme <i>carnitine palmitoyltransferase 1A</i> (<i>CPT1A</i>). FAO is an alternative fuel for ...[more]

PMID: 37788309

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Project description:BackgroundAbnormal expression of protein tyrosine phosphatases (PTPs) has been reported to be a crucial cause of cancer. As a member of PTPs, protein tyrosine phosphatase receptor type O (PTPRO) has been revealed to play tumor suppressive roles in several cancers, while its roles in colorectal cancer (CRC) remains to be elucidated. Hence, we aimed to explore the roles and mechanisms of PTPRO in CRC initiation and progression.MethodsThe influences of PTPRO on the growth and liver metastasis of CRC cells and the expression patterns of different lipid metabolism enzymes were evaluated in vitro and in vivo. Molecular and biological experiments were conducted to uncover the underpinning mechanisms of dysregulated de novo lipogenesis and fatty acid β-oxidation.ResultsPTPRO expression was notably downregulated in CRC liver metastasis compared to the primary cancer, and such a downregulation was associated with poor prognosis of patients with CRC. PTPRO silencing significantly promoted cell growth and liver metastasis. Compared with PTPRO wild-type mice, PTPRO-knockout mice developed more tumors and harbored larger tumor loads under treatment with azoxymethane and dextran sulfate sodium. Gene set enrichment analysis revealed that PTPRO downregulation was significantly associated with the fatty acid metabolism pathways. Blockage of fatty acid synthesis abrogated the effects of PTPRO silencing on cell growth and liver metastasis. Further experiments indicated that PTPRO silencing induced the activation of the AKT serine/threonine kinase (AKT)/mammalian target of rapamycin (mTOR) signaling axis, thus promoting de novo lipogenesis by enhancing the expression of sterol regulatory element-binding protein 1 (SREBP1) and its target lipogenic enzyme acetyl-CoA carboxylase alpha (ACC1) by activating the AKT/mTOR signaling pathway. Furthermore, PTPRO attenuation decreased the fatty acid oxidation rate by repressing the expression of peroxisome proliferator-activated receptor alpha (PPARα) and its downstream enzyme peroxisomal acyl-coenzyme A oxidase 1 (ACOX1) via activating the p38/extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) signaling pathway.ConclusionsPTPRO could suppress CRC development and metastasis via modulating the AKT/mTOR/SREBP1/ACC1 and MAPK/PPARα/ACOX1 pathways and reprogramming lipid metabolism.

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Nuclear VCP drives colorectal cancer progression by promoting fatty acid oxidation.

Publications

Nuclear VCP drives colorectal cancer progression by promoting fatty acid oxidation.

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