Reprogramming of palmitic acid induced by dephosphorylation of ACOX1 promotes β-catenin palmitoylation to drive colorectal cancer progression

Zhang, Qiang; Yang, Xiaoya; Wu, Jinjie; Ye, Shubiao; Cheng, Wai Ming; Luo, Zhanhao; Yu, Jing; Liu, Yugeng; Zeng, Wanyi; Liu, Chen; Xiong, Zhizhong; Chen, Yuan; He, Zhen; Lan, Ping

doi:10.1038/s41421-022-00515-x

Cited by 31 publications

(12 citation statements)

References 81 publications

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“…To explore the role of palmitoylation in STAT3 signaling, we treated cells with the palmitoylation inhibitor 2-Bromopalmitate (2-BP) [ 23 – 25 ] and the APT2 inhibitor ML349 [ 26 , 27 ]. 2-BP downregulated the level of STAT3 palmitoylation induced by LPS-PA, whereas ML349 upregulated it (Fig.…”

Section: Resultsmentioning

confidence: 99%

Dietary long-chain fatty acids promote colitis by regulating palmitoylation of STAT3 through CD36-mediated endocytosis

Wei,

Li,

et al. 2024

Cell Death Dis

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The Western diet, characterized by its high content of long-chain fatty acids (LCFAs), is widely recognized as a significant triggering factor for inflammatory bowel disease (IBD). While the link between a high-fat diet and colitis has been observed, the specific effects and mechanisms remain incompletely understood. Our study provides evidence that the diet rich in LCFAs can disrupt the integrity of the intestinal barrier and exacerbate experimental colitis in mice. Mechanistically, LCFAs upregulate the signal transducer and activator of transcription-3 (STAT3) pathway in the inflammatory model, and STAT3 knockout effectively counters the pro-inflammatory effects of LCFAs on colitis. Specifically, palmitic acid (PA), a representative LCFA, enters intestinal epithelial cells via the cluster of differentiation 36 (CD36) pathway and participates in the palmitoylation cycle of STAT3. Inhibiting this cycle using pharmacological inhibitors like 2-Bromopalmitate (2-BP) and ML349, as well as DHHC7 knockdown, has the ability to alleviate inflammation induced by PA. These findings highlight the significant role of dietary LCFAs, especially PA, in the development and progression of IBD. Diet adjustments and targeted modulation offer potential therapeutic strategies for managing this condition.

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Section: Resultsmentioning

confidence: 99%

Dietary long-chain fatty acids promote colitis by regulating palmitoylation of STAT3 through CD36-mediated endocytosis

Wei,

Li,

et al. 2024

Cell Death Dis

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“…The stability of ACOX1 is governed by DUSP14, which, through dephosphorylation, enhances ACOX1 degradation, thereby potentially accelerating CRC progression. This degradation leads to increased palmitoylation of β-linker proteins, furthering CRC advancement (Zhang et al 2023b ). CPT2, essential for fatty acid metabolism, is significantly downregulated in CRC, contributing to stem cell characteristics and oxaliplatin resistance.…”

Section: Discussionmentioning

confidence: 99%

Targeting nucleotide metabolic pathways in colorectal cancer by integrating scRNA-seq, spatial transcriptome, and bulk RNA-seq data

Zhao,

Zhang,

Niu

et al. 2024

Funct Integr Genomics

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Background Colorectal cancer is a malignant tumor of the digestive system originating from abnormal cell proliferation in the colon or rectum, often leading to gastrointestinal symptoms and severe health issues. Nucleotide metabolism, which encompasses the synthesis of DNA and RNA, is a pivotal cellular biochemical process that significantly impacts both the progression and therapeutic strategies of colorectal cancer Methods For single-cell RNA sequencing (scRNA-seq), five functions were employed to calculate scores related to nucleotide metabolism. Cell developmental trajectory analysis and intercellular interaction analysis were utilized to explore the metabolic characteristics and communication patterns of different epithelial cells. These findings were further validated using spatial transcriptome RNA sequencing (stRNA-seq). A risk model was constructed using expression profile data from TCGA and GEO cohorts to optimize clinical decision-making. Key nucleotide metabolism-related genes (NMRGs) were functionally validated by further in vitro experiments. Results In both scRNA-seq and stRNA-seq, colorectal cancer (CRC) exhibited unique cellular heterogeneity, with myeloid cells and epithelial cells in tumor samples displaying higher nucleotide metabolism scores. Analysis of intercellular communication revealed enhanced signaling pathways and ligand-receptor interactions between epithelial cells with high nucleotide metabolism and fibroblasts. Spatial transcriptome sequencing confirmed elevated nucleotide metabolism states in the core region of tumor tissue. After identifying differentially expressed NMRGs in epithelial cells, a risk prognostic model based on four genes effectively predicted overall survival and immunotherapy outcomes in patients. High-risk group patients exhibited an immunosuppressive microenvironment and relatively poorer prognosis and responses to chemotherapy and immunotherapy. Finally, based on data analysis and a series of cellular functional experiments, ACOX1 and CPT2 were identified as novel therapeutic targets for CRC. Conclusion In this study, a comprehensive analysis of NMRGs in CRC was conducted using a combination of single-cell sequencing, spatial transcriptome sequencing, and high-throughput data. The prognostic model constructed with NMRGs shows potential as a standalone prognostic marker for colorectal cancer patients and may significantly influence the development of personalized treatment approaches for CRC.

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“…In cancer, lipid metabolism is often modi ed, and studies have demonstrated that inhibiting lipid peroxidation can enhance CRC liver colonization in mouse models 12 . ACOX1, a key enzyme in fatty acid β-oxidation, acts as a tumor suppressor, and the downregulation of ACOX1 promotes CRC progression 13 . Carnitine palmitoyl transferase 1 (CPT1) controls the rate-limiting step of fatty acid oxidation (FAO).…”

Section: Introductionmentioning

confidence: 99%

Deficiency of SDHC promotes metastasis by reprogramming fatty acid metabolism in colorectal cancer

Ding,

Wei,

Dai

et al. 2024

Preprint

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Background Several studies have demonstrated a strong correlation between impaired Succinate dehydrogenase (SDH) function and the advancement of tumors. As a subunit of SDH, succinate dehydrogenase complex subunit C (SDHC) has been revealed to play tumor suppressive roles in several cancers, while its specific role in colorectal cancer (CRC) still needs further investigation. Methods The effects of SDHC on the metastasis of CRC cells were evaluated both in vitro and in vivo. To reveal the mechanisms underlying SDHC, drug screening and RNA sequencing were carried out. Molecular and biological experiments were conducted to uncover the mechanisms of dysregulated lipid accumulation caused by SDHC. Results Downregulation of SDHC was found to be closely associated with a poor prognosis in CRC. SDHC knockdown promoted CRC metastasis both in vitro and in vivo. Through drug screening and Gene set enrichment analysis, it was discovered that SDHC downregulation was positively associated with the fatty acid metabolism pathways significantly. The effects of SDHC silencing on metastasis were reversed when fatty acid synthesis was blocked. Subsequent experiments revealed that SDHC silencing activated the PI3K/AKT signaling axis, leading to lipid accumulation by upregulating the expression of aldehyde dehydrogenase 3 family member A2 (ALDH3A2) and reduction of fatty acid oxidation rate by suppressing the expression of acyl-coenzyme A oxidase 1 (ACOX1) and carnitine palmitoyltransferase 1A (CPT1A). Conclusions SDHC deficiency could potentially enhance CRC metastasis by modulating the PI3K/AKT pathways and reprogramming lipid metabolism.

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Reprogramming of palmitic acid induced by dephosphorylation of ACOX1 promotes β-catenin palmitoylation to drive colorectal cancer progression

Cited by 31 publications

References 81 publications

Dietary long-chain fatty acids promote colitis by regulating palmitoylation of STAT3 through CD36-mediated endocytosis

Dietary long-chain fatty acids promote colitis by regulating palmitoylation of STAT3 through CD36-mediated endocytosis

Targeting nucleotide metabolic pathways in colorectal cancer by integrating scRNA-seq, spatial transcriptome, and bulk RNA-seq data

Deficiency of SDHC promotes metastasis by reprogramming fatty acid metabolism in colorectal cancer

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