FASN promotes lymph node metastasis in cervical cancer via cholesterol reprogramming and lymphangiogenesis

Du, Qiqiao; Liu, Pan; Zhang, Chunyu; Li, Tianyu; Wang, Wei; Shang, Chunliang; Wu, Jing‐Ming; Liao, Yuandong; Chen, Yili; Huang, Jiaming; Tan, Hao; Zhao, Yunhe; Xia, Meng; Liu, Junxiu; Yao, Shuzhong

doi:10.1038/s41419-022-04926-2

Cited by 49 publications

(35 citation statements)

References 47 publications

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“…In particular, FASN expression in CESC showed a significant increase in both stage and grade, and Shang et al demonstrated that targeting FASN by the combination of miR-532-5p and the FASN inhibitor orlistat significantly inhibited lymph node metastasis in cervical cancer mouse xenografts [ 21 ]. Moreover, Du et al also showed that FASN can promote lymph node metastasis in cervical cancer through cholesterol re-programming and lymphangiogenesis [ 22 ], further demonstrating that FASN was associated with the malignant progression of CESC. Overall, we speculated that up-regulation of FASN in tumors maybe promote tumor progression.…”

Section: Resultsmentioning

confidence: 99%

Comprehensive Analysis of FASN in Tumor Immune Infiltration and Prognostic Value for Immunotherapy and Promoter DNA Methylation

Zhang

Sun

et al. 2022

IJMS

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Fatty acid synthase (FASN) promotes tumor progression in multiple cancers. In this study, we comprehensively examined the expression, prognostic significance, and promoter methylation of FASN, and its correlation with immune cell infiltration in pan-cancer. Our results demonstrated that elevated FASN expression was significantly associated with an unfavorable prognosis in many cancer types. Furthermore, FASN promoter DNA methylation can be used as a tumor prognosis marker. Importantly, high levels of FASN were significantly negatively correlated with tumor immune infiltration in 35 different cancers. Additionally, FASN was significantly associated with tumor mutational burden (TMB) and microsatellite instability (MSI) in multiple malignancies, suggesting that it may be essential for tumor immunity. We also investigated the effects of FASN expression on immunotherapy efficacy and prognosis. In up to 15 tumors, it was significantly negatively correlated with immunotherapy-related genes, such as PD-1, PD-L1, and CTLA-4. Moreover, we found that tumors with high FASN expression may be more sensitive to immunotherapy and have a good prognosis with PD-L1 treatment. Finally, we confirmed the tumor-suppressive effect of mir-195-5p through FASN. Altogether, our results suggested that FASN may serve as a novel prognostic indicator and immunotherapeutic target in various malignancies.

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Section: Resultsmentioning

confidence: 99%

Comprehensive Analysis of FASN in Tumor Immune Infiltration and Prognostic Value for Immunotherapy and Promoter DNA Methylation

Zhang

Sun

et al. 2022

IJMS

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“…KDM5C is a histone H3K4-specific demethylase, and the overexpression of KDM5C led to the reduction of H3K4me3 on the promoter and the corresponding downregulation of FASN expression to inhibit FASN-mediated lipid metabolism ( Zhang et al, 2020 ). Du et al (2022 ) illustrated that FASN can promote the lymph node metastasis of cervical cancer via cholesterol reprogramming and lymph angiogenesis. The mechanisms of how histone modification influences the tumorigenesis of cervical cancer are complicated and need a further in-depth study.…”

Section: Discussionmentioning

confidence: 99%

Assessment of alterations in histone modification function and guidance for death risk prediction in cervical cancer patients

et al. 2022

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Background: Cervical cancer is the second most lethal malignancy among women, and histone modification plays a fundamental role in most biological processes, but the prognostic value of histone modification in cervical cancer has not been evaluated.Methods: A total of 594 cervical cancer patients from TCGA-CESC, GSE44001, and GSE52903 cohorts were enrolled in the current study, along with the corresponding clinicopathological features. Patients with a follow-up time less than one month were removed. A total of 122 histone modification-associated signaling pathways were obtained from the MSigDB. The activation scores of these pathways were evaluated using the “GSVA” package, differentially expressed genes were identified by the “limma” package, and pathway enrichment was conducted using the “clusterProfiler 4.0” package. The subsequent least absolute shrinkage and selection operator (LASSO) regression analysis was performed using the “glmnet” package, and a prognostic nomogram was established using the “regplot” package. For the prediction of potential therapeutic drugs, we used the data from GDSC2016 and visualized them via “MOVICS”.Results: Nine of 23 histone modification-associated prognostic genes were identified to construct the prognostic signature by LASSO analysis, named the histone modification-associated gene (HMAG) signature. Cervical patients with HMAG-H in TCGA-CESC cohort showed a 2.68-fold change of death risk, with the 95% CI from 1.533 to 4.671 (p < 0.001), as well as the increased death risk of HMAG-H in the GSE44001 cohort (HR: 2.83, 95% CI: 1.370–5.849, p = 0.005) and GSE44001 cohort (HR: 4.59, 95% CI: 1.658–12.697, p = 0.003). We observed the preferable AUC values of the HMAG signature in TCGA-CESC cohort (1-year: 0.719, 3-year: 0.741, and 5-year: 0.731) and GSE44001 cohort (1-year: 0.850, 3-year: 0.781, and 5-year: 0.755). The C-index of the nomogram showed a prognostic value as high as 0.890, while the C-index for age was only 0.562, and that for grade was only 0.542. Patients with high HMAG scores were more suitable for the treatment of CHIR-99021, embelin, FTI-277, JNK-9L, JQ12, midostaurin, PF-562271, pyrimethamine, and thapsigargin, and patients with low HMAG scores were more suitable for the treatment of BMS-536924, CP466722, crizotinib, PHA-665752, rapamycin, and TAE684.Conclusion: We comprehensively evaluated the histone modification status in cervical cancer patients and revealed histone modification-associated prognostic genes to construct the HMAG signature, aiming to provide a new insight into prognosis prediction and precise clinical treatment.

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“…Dis-regulated cholesterol homeostasis resulted in resistance to ferroptosis and increased cancer metastasis [74]. Indeed, abnormal cholesterol and lipid metabolisms in tumor cells might facilitate lymph node metastasis, such as enhanced fatty acid synthase in cervical cancer [75], and the adaptation of lipid metabolism to fatty acid oxidation that has been found required for lymph node metastasis [76]. Therefore, future works are necessary to elucidate the mechanisms underlying FOXO3-GULP1 axis-mediated cholesterol and lipid metabolisms to promote lymph node metastasis in UBC.…”

Section: Forkhead Box Class O (Foxo) Proteins Represent a Family Of E...mentioning

confidence: 99%

The APC/C E3 ligase subunit ANAPC11 mediates FOXO3 protein degradation to promote cell proliferation and lymph node metastasis of urothelial bladder cancer

Yan

Pei

et al. 2023

Preprint

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Urothelial bladder cancer (UBC) is one of the most prevalent malignancies worldwide with striking tumor heterogeneity. Elucidating the molecular mechanism for the treatment of aggressive UBC is particularly relevant. Protein ubiquitination is critical constitution of post-translational modification (PTM) that mediates the degradation of target protein through proteasome. However, the roles of aberrant protein ubiquitination in UBC development and the underlying mechanism in driving tumor progression remain unclear. In this study, taking the advantage of CRISPR/Cas9 technology, we identified ubiquitin E3 ligase ANAPC11, a critical subunit of anaphase-promoting complex/cyclosome (APC/C), as a potential oncogenic molecule in UBC cells. Our clinical analysis showed that the elevated expression of ANAPC11 was significantly correlated with high T stage, positive lymph node metastasis and poor outcomes of UBC patients. By employing a series of in vitro experiments, we demonstrated that ANAPC11 boosted the proliferation and invasiveness of UBC cells, while knockout of ANAPC11 inhibited the growth and lymph node metastasis of UBC cells in vivo. By conducting immunoprecipitation coupled to mass spectrometry assays, we confirmed that ANAPC11 increased the ubiquitination level of Forkhead transcription factor FOXO3. As a result, the decrease of FOXO3 protein stability led to the down-regulation of the cell cycle regulator p21 and the abrogation of GULP1, a downstream effector of androgen receptor signaling. Taken together, ANAPC11 showed oncogenic functions in UBC by modulating the FOXO3 protein degradation. ANAPC11-FOXO3 regulatory axis might serve as a novel therapeutic target for UBC.

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FASN promotes lymph node metastasis in cervical cancer via cholesterol reprogramming and lymphangiogenesis

Cited by 49 publications

References 47 publications

Comprehensive Analysis of FASN in Tumor Immune Infiltration and Prognostic Value for Immunotherapy and Promoter DNA Methylation

Comprehensive Analysis of FASN in Tumor Immune Infiltration and Prognostic Value for Immunotherapy and Promoter DNA Methylation

Assessment of alterations in histone modification function and guidance for death risk prediction in cervical cancer patients

The APC/C E3 ligase subunit ANAPC11 mediates FOXO3 protein degradation to promote cell proliferation and lymph node metastasis of urothelial bladder cancer

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