Acyl-CoA Thioesterase 8 (ACOT8) is a Poor Prognostic Biomarker in Breast Cancer.

Purpose: This study aimed to investigate the expression of Acyl-CoA thioesterase 8 (ACOT8) in breast cancer (BC) and its association with clinicopathological characteristics, patient survival, and immune infiltration. Methods: We conducted a comprehensive analysis of ACOT8 mRNA differential expression across various cancer types, followed by survival analysis. We focused on BC, where ACOT8 expression was evaluated at both the mRNA and protein levels using online databases, qRT-PCR, and immunohistochemistry. Associations between ACOT8 expression and clinicopathological parameters were assessed using different databases. Additionally, we investigated the prognostic significance of ACOT8 in BC patients by analyzing various cohorts and databases. Furthermore, we predicted a potential signaling pathway and identified miR-1-3p as a possible upstream regulator of ACOT8. Finally, the relationship between ACOT8 and immune system infiltration, as well as immune checkpoint molecules, was examined. Results: Our findings demonstrated upregulated ACOT8 mRNA and protein levels in BC. Elevated ACOT8 expression correlated positively with various clinicopathological characteristics, indicating an unfavorable prognosis for patients. Functional enrichment analysis suggested ACOT8 involvement in lipid metabolism, mitochondrial components, and ribosomal functions. Moreover, we identified connections between ACOT8 and immune system markers, immune cell infiltration, and immune checkpoints. Conclusion: This study provides compelling evidence for ACOT8 upregulation in BC and its association with clinicopathological features and patient outcomes. Additionally, our findings suggest that targeting ACOT8 and immune checkpoints might enhance the effectiveness of immunotherapy in BC patients.

TSC22D2 Regulates ACOT8 to Delay the Malignant Progression of Colorectal Cancer.

Purpose: Colorectal cancer (CRC) is one of the cancers with high incidence and mortality rates worldwide. In China, there are approximately 400,000 new CRC cases each year, seriously endangering people's life and health. Transforming growth factor ß-stimulated clone 22 domain family, member 2 (TSC22D2) is widely expression in cancers, but the role of TSC22D2 in CRC are still unknown. Methods: Real­time quantitative PCR (qRT-PCR) and Western blot were applied to determine the TSC22D2 levels. CCK-8, colony formation and transwell assays were used to determine the proliferation and metastasis abilities of CRC cells in vitro. In vivo metastatic potential was assessed using a subcutaneously injected mouse model and. Western-blot and immunoprecipitation experiments were used to study the mechanism of TSC22D2­mediated metastasis. Results: We found TSC22D2 was deregulated in CRC tissues and cells and implied poor prognosis. Overexpression TSC22D2 significantly promoted CRC cells proliferation and tumorigenicity both in vitro and vivo, whereas knockdown TSC22D2 resulted in the opposite effects. Importantly using a co-immunoprecipitation (co-IP) assay combined with mass spectrometry analysis to identify TSC22D2-interacting acyl-coenzyme A thioesterases 8 (ACOT8), TSC22D2 maintained stability of ACOT8. Overexpression of TCC22D2 in CRC cells can promote the expression of ACOT8 and inhibit the proliferation and metastasis of CRC cells through EMT mechanism, highlighting the possibility of TSC22D2 as a potential target in CRC development. Conclusion: In summary, the present study revealed the inhibitory effect of TSC22D2 on the proliferation of colorectal cancer cells, suggesting that TSC22D2 may be an important tumor suppressor and a potential therapeutic target during colorectal carcinogenesis.

Hepatic conversion of acetyl-CoA to acetate plays crucial roles in energy stress.

Accumulating evidence indicates that acetate is increased under energy stress conditions such as those that occur in diabetes mellitus and prolonged starvation. However, how and where acetate is produced and the nature of its biological significance are largely unknown. We observed overproduction of acetate to concentrations comparable to those of ketone bodies in patients and mice with diabetes or starvation. Mechanistically, ACOT12 and ACOT8 are dramatically upregulated in the liver to convert free fatty acid-derived acetyl-CoA to acetate and CoA. This conversion not only provides a large amount of acetate, which preferentially fuels the brain rather than muscle, but also recycles CoA, which is required for sustained fatty acid oxidation and ketogenesis. We suggest that acetate is an emerging novel 'ketone body' that may be used as a parameter to evaluate the progression of energy stress.

Acyl-CoA Thioesterase 8 and 11 as Novel Biomarkers for Clear Cell Renal Cell Carcinoma.

BACKGROUND: Clear cell renal cell carcinoma (ccRCC) is essentially a metabolic disorder characterized by reprogramming of several metabolic pathways. Acyl-coenzyme A thioesterases (ACOTs) are critical enzymes involved in fatty acid metabolism; however, the roles of ACOTs in ccRCC remain unclear. This study explored ACOTs expressions and their diagnostic and prognostic values in ccRCC. METHODS: Three online ccRCC datasets from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) were utilized to measure the expressions of ACOTs in paired normal and tumor tissues. Receiver operating characteristic (ROC) curves were depicted to assess the diagnostic values of ACOTs in ccRCC. Quantitative real-time PCR and immunohistochemical analysis were performed to validate the ACOT11 expression in ccRCC cell lines and clinical samples. Survival curves and Cox regression analysis were used to evaluate the predictive values of ACOTs in clinical outcome of ccRCC patients. Functional enrichment analyses and correlation analysis were carried out to predict the potential roles of ACOT8 in tumorigenesis and progression of ccRCC. RESULTS: ACOT1/2/8/11/13 were found to be significantly downregulated in ccRCC samples. In particular, ACOT11 was decreased in almost every matched normal-tumor pair, and had extremely high diagnostic value as shown by ROC curve analysis (AUC = 0.964). The expression of ACOT11 was further verified in ccRCC cell lines and clinical samples at mRNA and protein levels. Furthermore, clinical correlation analysis and survival analysis indicated that ACOT8 was correlated with disease progression and was an independent predictor of unfavorable outcome in ccRCC. Moreover, functional analyses suggested potential roles of ACOT8 in the regulation of oxidative phosphorylation (OXPHOS), and correlation analysis revealed an association between ACOT8 and ferroptosis-related genes in ccRCC. CONCLUSION: Our study revealed that ACOT11 and ACOT8 are promising biomarkers for diagnosis and prognosis of ccRCC, respectively, and ACOT8 may affect ccRCC development and progression through the regulation of OXPHOS and ferroptosis. These findings may provide new strategies for precise diagnosis and personalized therapy of ccRCC.

Physiological relevance of ACOT8-Nef interaction in HIV infection.

During human immunodeficiency virus (HIV) infection, Nef viral protein plays a crucial role in viral pathogenesis and progression of acquired immunodeficiency syndrome. Nef is expressed in the early stages of infection and alters the cellular environment increasing infectivity, viral replication, and the evasion of host immune response through several mechanisms. Nef has numerous functional domains that allow it to interact with a number of proteins, interfering with intracellular traffic. Among these proteins, human peroxisomal thioesterase 8, ACOT8, has been shown to be an important cellular partner of Nef. It has been suggested that this interaction may be involved in Nef-dependent endocytosis and also in the modulation of lipid composition in membrane rafts. However, the actual role of this interaction, as well as the mechanisms involved, has not yet been fully elucidated. In this review, we focused on the interplay between Nef and ACOT8 proteins, highlighting the possible physiological relevance in HIV infection.

The role of acyl-CoA thioesterase ACOT8I in mediating intracellular lipid metabolism in oleaginous fungus Mortierella alpina.

Thioesterases (TEs) play an essential role in the metabolism of fatty acids (FAs). To explore the role of TEs in mediating intracellular lipid metabolism in the oleaginous fungus Mortierella alpina, the acyl-CoA thioesterase ACOT8I was overexpressed. The contents of total fatty acids (TFAs) were the same in the recombinant strains as in the wild-type M. alpina, whilst the production of free fatty acids (FFAs) was enhanced from about 0.9% (wild-type) to 2.8% (recombinant), a roughly threefold increase. Linoleic acid content in FFA form constituted about 9% of the TFAs in the FFA fraction in the recombinant strains but only about 1.3% in the wild-type M. alpina. The gamma-linolenic acid and arachidonic acid contents in FFA form accounted for about 4 and 25%, respectively, of the TFAs in the FFA fraction in the recombinant strains, whilst neither of them in FFA form were detected in the wild-type M. alpina. Overexpression of the TE ACOT8I in the oleaginous fungus M. alpina reinforced the flux from acyl-CoAs to FFAs, improved the production of FFAs and tailored the FA profiles of the lipid species.