Liver ACSM3 deficiency mediates metabolic syndrome via a lauric acid-HNF4α-p38 MAPK axis.

Metabolic syndrome combines major risk factors for cardiovascular disease, making deeper insight into its pathogenesis important. We here explore the mechanistic basis of metabolic syndrome by recruiting an essential patient cohort and performing extensive gene expression profiling. The mitochondrial fatty acid metabolism enzyme acyl-CoA synthetase medium-chain family member 3 (ACSM3) was identified to be significantly lower expressed in the peripheral blood of metabolic syndrome patients. In line, hepatic ACSM3 expression was decreased in mice with metabolic syndrome. Furthermore, Acsm3 knockout mice showed glucose and lipid metabolic abnormalities, and hepatic accumulation of the ACSM3 fatty acid substrate lauric acid. Acsm3 depletion markedly decreased mitochondrial function and stimulated signaling via the p38 MAPK pathway cascade. Consistently, Acsm3 knockout mouse exhibited abnormal mitochondrial morphology, decreased ATP contents, and enhanced ROS levels in their livers. Mechanistically, Acsm3 deficiency, and lauric acid accumulation activated nuclear receptor Hnf4α-p38 MAPK signaling. In line, the p38 inhibitor Adezmapimod effectively rescued the Acsm3 depletion phenotype. Together, these findings show that disease-associated loss of ACSM3 facilitates mitochondrial dysfunction via a lauric acid-HNF4a-p38 MAPK axis, suggesting a novel therapeutic vulnerability in systemic metabolic dysfunction.

Acquisition of taxane resistance by p53 inactivation in ovarian cancer cells.

Ovarian cancer is one of the most common gynecologic malignancies in women and has a poor prognosis. Taxanes are a class of standard first-line chemotherapeutic agents for the treatment of ovarian cancer. However, tumor-intrinsic and acquired resistance to taxanes poses major challenges to improving clinical outcomes. Hence, there is an urgent clinical need to understand the mechanisms of resistance in order to discover potential biomarkers and therapeutic strategies to increase taxane sensitivity in ovarian cancer. Here, we report the identification of an association between the TP53 status and taxane sensitivity in ovarian cancer cells through complementary experimental and informatics approaches. We found that TP53 inactivation is associated with taxane resistance in ovarian cancer cells, supported by the evidence from (i) drug sensitivity profiling with bioinformatic analysis of large-scale cancer therapeutic response and genomic datasets and (ii) gene signature identification based on experimental isogenic cell line models. Further, our studies revealed TP53-dependent gene expression patterns, such as overexpression of ACSM3, as potential predictive biomarkers of taxane resistance in ovarian cancer. The TP53-dependent hyperactivation of the WNT/ß-catenin pathway discovered herein revealed a potential vulnerability to exploit in developing combination therapeutic strategies. Identification of this genotype-phenotype relationship between the TP53 status and taxane sensitivity sheds light on TP53-directed patient stratification and therapeutic discoveries for ovarian cancer treatment.

Acyl-CoA Medium-Chain Synthetase-3 (ACSM3) Is Regulated by Insulin Like Growth Factor 2 mRNA Binding Protein 3 (IGF2BP3) and Inhibits Proliferation, Motility and Stem Cell Properties of Breast Invasive Carcinoma.

OBJECTIVE: Breast invasive carcinoma (BRCA) has a high degree of malignancy, is prone to lymph node metastasis, and has a poor prognosis. This study aimed to explore the role of Acyl-CoA Medium-Chain Synthetase-3 (ACSM3) in BRCA, which was found down-regulated in liver cancer and malignant melanoma. METHODS: The expression level of ACSM3 in patients with BRCA and its correlation with the overall survival rate was analyzed. The impacts of ACSM3 on BRCA cell proliferation, motility and stem cell properties were then evaluated. The association between insulin like growth factor 2 mRNA binding protein 3 (IGF2BP3) and ACSM3 was verified, the influences of IGF2BP3 on the regulation of ACSM3 on cells were determined. RESULTS: Down-regulated ACSM3 level was associated with poor overall survival. ACSM3 overexpression weakened BRCA cell proliferation, motility and stem cell properties. Importantly, IGF2BP3 destabilized ACSM3 and downregulated its expression level. IGF2BP3 overexpression reversed the impacts of ACSM3 overexpression on cells, indicating that ACSM3 was regulated by IGF2BP3 in BRCA cells. CONCLUSION: We found that ACSM3 was regulated by IGF2BP3 and attenuated BRCA proliferation, invasion and stem cell properties. The role of ACSM3 in BRCA was first revealed, which provides a novel target for treatment.

ACSM3 suppresses the pathogenesis of high-grade serous ovarian carcinoma via promoting AMPK activity.

PURPOSE: Ovarian carcinoma is the fifth commonest malignancy in females and exhibits a high recurrence rate. High-grade serous ovarian carcinoma (HGSOC) is the main histologic subtype. It displays extensive genetic heterogeneity. Here, we aimed to identify potential therapeutic targets for HGSOC. METHODS: Both bioinformatic data from TCGA and 73 pairs of tumor and normal samples from patients were analyzed to reveal the expression level of ACSM3 in HGSOC. Next, cellular and animal experiments, including cell proliferation, colony formation and xenograft assays were performed to explore the suppressive function of ACSM3. Finally, biochemical methods, AMP/ATP ratio measurements and Western blotting were used to elucidate the mechanism underlying the ACSM3-AMPK axis in HGSOC. RESULTS: After analyzing transcriptome data of TCGA HGSOC samples, we found that ACSM3 is down-regulated in patient samples compared with normal controls. This observation was validated using data from primary clinical samples. Proliferation, soft agar colony formation and xenograft assays revealed that ACSM3 is able to suppress HGSOC tumor growth both in vitro and in vivo. Moreover, we found that ACSM3 overexpression increased the AMP/ATP ratio and the phosphorylation level of AMPK at threonine 172. In addition, we found that AMPK silencing in EFO21 and SKOV3 cells completely abolished the anti-oncogenic effect of ACSM3. CONCLUSION: Our data indicate that the ACSM3-AMPK axis is involved in the pathogenesis of HGSOC and, as such, may act as a therapeutic target for this cancer.

Hepatic Transcriptome Profiling Reveals Lack of Acsm3 Expression in Polydactylous Rats with High-Fat Diet-Induced Hypertriglyceridemia and Visceral Fat Accumulation.

Metabolic syndrome (MetS) is an important cause of worldwide morbidity and mortality. Its complex pathogenesis includes, on the one hand, sedentary lifestyle and high caloric intake, and, on the other hand, there is a clear genetic predisposition. PD (Polydactylous rat) is an animal model of hypertriglyceridemia, insulin resistance, and obesity. To unravel the genetic and pathophysiologic background of this phenotype, we compared morphometric and metabolic parameters as well as liver transcriptomes among PD, spontaneously hypertensive rat, and Brown Norway (BN) strains fed a high-fat diet (HFD). After 4 weeks of HFD, PD rats displayed marked hypertriglyceridemia but without the expected hepatic steatosis. Moreover, the PD strain showed significant weight gain, including increased weight of retroperitoneal and epididymal fat pads, and impaired glucose tolerance. In the liver transcriptome, we found 5480 differentially expressed genes, which were enriched for pathways involved in fatty acid beta and omega oxidation, glucocorticoid metabolism, oxidative stress, complement activation, triacylglycerol and lipid droplets synthesis, focal adhesion, prostaglandin synthesis, interferon signaling, and tricarboxylic acid cycle pathways. Interestingly, the PD strain, contrary to SHR and BN rats, did not express the Acsm3 (acyl-CoA synthetase medium-chain family member 3) gene in the liver. Together, these results suggest disturbances in fatty acid utilization as a molecular mechanism predisposing PD rats to hypertriglyceridemia and fat accumulation.

Loss of ACSM3 confers worsened prognosis and immune exclusion to cutaneous melanoma.

Aim: Malignant melanoma (MM) is a highly aggressive cutaneous cancer with undetermined underlying genetic disposition. We aim to evaluate prognostic and mechanistic role of ACSM3 in MM. Methods: In silico reproduction of TCGA MM dataset, GEO dataset, GDSC dataset and human protein atlas was performed to establish differential expression of ACSM3. In vitro and in vivo validation using A375 and SKMEL1 MM cells were performed to profile tumorigenic role and functional attribution of the gene. Results: ACSM3 expression was significantly downregulated in MM. Lower expression of ACSM3 conferred worsened prognosis of MM. Lower ACSM3 was observed in Asian ethnicity. Knock-down (KD) and overexpression (OE) of ACSM3 resulted in significant increased and decreased proliferation, invasion and colony formation in MM cells, respectively. Pathway annotation revealed significantly active immune response invoked by ACSM3. Lower ACSM3 expression was associated with decreased CD8+, macrophage and dendritic cell infiltration. Cox regression revealed loss of survival contribution of ACSM3 in the presence of immune infiltrates supporting immune regulatory role of ACSM3. Drug sensitivity analysis revealed BRAF inhibitor PLX-4720 was sensitive in both MM cells. ACSM3 expression showed no correlation with immune checkpoint molecules. Combined ACSM3-OE and PLX-4720 in MM cells showed synergistic inhibition in MM cells and xenograft murine models with no significant toxicity. Conclusion: Loss of ACSM3 was associated with poor prognosis in MM. Overexpression of ACSM3 synergistically inhibited MM with PLX-4720. ACSM3 was potentially associated with immune exclusion in MM. Further validation was warranted in future studies.

Downregulation of ACSM3 promotes metastasis and predicts poor prognosis in hepatocellular carcinoma.

Understanding mechanisms of cancer metastasis is crucial for reduction of cancer mortality. Acyl-CoA medium-chain synthetase 3 (ACSM3) is an acyl-CoA synthetase which takes part in the first step of fatty acid metabolism. However, the expression, clinical significance and biological function of ACSM3 remain unknown in hepatocellular carcinoma (HCC). In this study, the expression and prognostic relevance of ACSM3 were investigated by tissue microarray and HCC clinical samples. Migration and invasion assays were carried out for functional analysis in vitro and a xenograft model was used to analyze the effects of ACSM3 on cancer metastasis in vivo. Furthermore, human phospho-kinase array assays were performed to explore molecular mechanisms of ACSM3 in HCC. The results showed ACSM3 was downregulated in HCC tissues. HCC patients with low expression of ACSM3 exhibited poor prognosis. Overexpression of ACSM3 attenuated migration and invasion of HCC cells in vitro and in vivo and downregulated the phosphorylation of WNK1 and AKT. Our findings indicate ACSM3 is a novel prognostic marker and a potential therapeutic target for HCC.

Integrative transcriptome analysis of liver cancer profiles identifies upstream regulators and clinical significance of ACSM3 gene expression.

PURPOSE: Hepatocellular carcinoma (HCC) is one of the most common human malignancies. It has frequently been associated with metabolic perturbations and liver damages. Various members of the family of acyl-CoA synthetases are known to be involved in the production of bioactive fatty acids, and altered expression of its encoding genes has been found to be involved in metabolic perturbations. For the development of novel diagnostic and therapeutic HCC options, a fundamental understanding of the mechanisms associated with the deregulation of candidate genes involved in metabolic perturbation is required. METHODS: A meta-analysis of multiple HCC mRNA profiles was performed to identify consistently deregulated genes. Expression of the acyl-CoA synthetase medium chain family member 3 (ACSM3) gene was subsequently assessed in different HCC tumor stages and correlated with various clinicopathological features. Transcription regulation, survival and pathway-associated features of the ACSM3 gene were investigated using integrative functional genomic and molecular cell biological methods. RESULTS: We found that expression of the ACSM3 gene was significantly reduced in HCC tissues and was frequently downregulated in patients exhibiting high alpha-fetoprotein (AFP) levels, high alanine aminotransferase (ALT) levels, multiple nodules and large tumors. Loss of ACSM3 expression was found to correlate with advanced HCC stages and a poor survival. In addition, HNF4α was found to positively regulate the expression of the ACSM3 gene, while PPARγ was found to transcriptionally repress it. Downregulation of ACSM3 expression was perceived upon activation of the TGFß, WNT, AKT and MYC signalling pathways. In addition, we found that ACSM3 expression correlates with fatty acid oxidation in HCC. CONCLUSION: Our data provide evidence for a differential expression and regulation of the ACSM3 gene in HCC, and may lay a foundation for therapeutically targeting fatty acid metabolism in these tumors.