FASN

Gene Summary

Gene:FASN; fatty acid synthase
Aliases: FAS, OA-519, SDR27X1
Location:17q25.3
Summary:The enzyme encoded by this gene is a multifunctional protein. Its main function is to catalyze the synthesis of palmitate from acetyl-CoA and malonyl-CoA, in the presence of NADPH, into long-chain saturated fatty acids. In some cancer cell lines, this protein has been found to be fused with estrogen receptor-alpha (ER-alpha), in which the N-terminus of FAS is fused in-frame with the C-terminus of ER-alpha. [provided by RefSeq, Jul 2008]
Databases:VEGA, OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:fatty acid synthase
Source:NCBIAccessed: 11 March, 2017

Ontology:

What does this gene/protein do?
Show (33)
Pathways:What pathways are this gene/protein implicaed in?
Show (2)

Cancer Overview

Research Indicators

Publications Per Year (1992-2017)
Graph generated 11 March 2017 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 11 March, 2017 using data from PubMed, MeSH and CancerIndex

Specific Cancers (6)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications: FASN (cancer-related)

Bauer G
Central Signaling Elements of Intercellular Reactive Oxygen/Nitrogen Species-dependent Induction of Apoptosis in Malignant Cells.
Anticancer Res. 2017; 37(2):499-513 [PubMed] Related Publications
Intercellular reactive oxygen/reactive nitrogen species-(ROS/RNS)-dependent induction of apoptosis in malignant cells is discussed as a potential control step during oncogenesis. In previous studies, the mechanism of intercellular apoptosis-inducing signaling was mainly established through the use of specific inhibitors and scavengers. Here, a detailed analysis was carried out based on small interfering ribonucleic acid (siRNA)-mediated knockdown of central players of intercellular ROS/RNS signaling and of the mitochondrial and the FAS receptor-dependent pathway of apoptosis. The data show that transforming growth factor β1, transforming growth factor β receptor, NADPH oxidase-1 (NOX1), NOX1 organizer, and NOX1 activator control the HOCl and the NO/peroxynitrite signaling pathways. Dual oxidase-1 (DUOX1) is specifically involved in HOCl signaling, and NO synthase in NO/peroxynitrite signaling. Both pathways utilize intracellular signal transduction through protein kinase C zeta, sphingomyelinase and central elements of the mitochondrial pathway of apoptosis, whereas the FAS receptor and FAS ligand do not seem to play a role.

Jiang Z, Shen H, Tang B, et al.
Quantitative proteomic analysis reveals that proteins required for fatty acid metabolism may serve as diagnostic markers for gastric cancer.
Clin Chim Acta. 2017; 464:148-154 [PubMed] Related Publications
BACKGROUND: Gastric cancer is one of the leading causes of cancer-related deaths worldwide. The sensitivities and specificities of current biomarkers for gastric cancer are insufficient for clinical detection, and new diagnostic tests are therefore urgently required.
METHODS: A discovery set of gastric cancer and adjacent normal tissues were analyzed for differentially expressed proteins by labeling of peptide digests with isobaric tag for relative and absolute quantitation (iTRAQ) reagents followed by liquid chromatography-electrospray ionization-tandem mass spectrometry. A validation set of 70 pairs of gastric cancer and adjacent normal tissues were examined to confirm the expression levels of the potential biomarkers identified by iTRAQ labeling.
RESULTS: We detected 431 proteins associated with 16 KEGG pathways that were differentially expressed in gastric cancer tissues, of which 224 were upregulated and 207 were downregulated in gastric cancer tissues. Coexpression of fatty acid binding protein (FABP1) and fatty acid synthase (FASN) in gastric cancer tissues (61.4% sensitivity and 77.1% specificity) was strongly associated with lymph node metastasis and Tumor, Node, Metastasis stage I/II.
CONCLUSION: Quantitative proteomic analysis of gastric cancer tissues revealed that coexpression of FABP1 and FASN may serve as a biomarker for detection of early gastric cancer.

Zhang H, Wang F, Hu Y
STARD13 promotes hepatocellular carcinoma apoptosis by acting as a ceRNA for Fas.
Biotechnol Lett. 2017; 39(2):207-217 [PubMed] Related Publications
OBJECTIVES: To study the roles of STARD13 in cellular apoptosis of hepatocellular carcinoma (HCC).
RESULTS: Quantitative real-time PCR and immunohistochemistry analyses showed that the expression levels of STARD13 and Fas were lower in clinical HCC tissues than in normal tissues and were positively correlated, which is consistent with the results analyzed by The Cancer Genome Atlas (TCGA) data. Patients with higher STARD13 or Fas expression levels had longer overall survival. Additionally, STARD13 3'-UTR enhanced cellular apoptosis and the 3'-UTRs of STARD13 and Fas were predicted to harbor nine similar miRNA binding sites. And STARD13 3'-UTR promoted Fas expression in a 3'-UTR- and miRNA-dependent way and increased the sensitivity of HCC cells to chemotherapy. Importantly, the coding sequence of STARD13 did not increase Fas expression.
CONCLUSIONS: STARD13 3'-UTR promotes HCC apoptosis through acting as a ceRNA for Fas.

Zhou Y, Jin G, Mi R, et al.
Inhibition of fatty acid synthase suppresses neovascularization via regulating the expression of VEGF-A in glioma.
J Cancer Res Clin Oncol. 2016; 142(12):2447-2459 [PubMed] Related Publications
PURPOSE: Fatty acids (FAs) are essential for membrane lipids biosynthesis and energy consumption in cancer cells. De novo FAs synthesis is catalyzed by fatty acid synthase (FASN), which is overexpressed and correlates with histological grade in glioma. Herein, we focused on the role of FASN in glioma neovascularization.
METHODS: The expression levels of FASN, Ki67 and CD34 were determined using immunohistochemistry (IHC). FASN specific-targeted shRNA and C75 were applied to evaluate the influence of FASN on glioma stem cell proliferation, migration and tube formation ability in vitro. An intracranial glioma model was established to study the effects of FASN on tumor growth and neovascularization in vivo.
RESULTS: IHC staining showed that the expression level of FASN correlated with tumor grade, Ki67 levels and microvessels density (MVD) in human gliomas. Inhibition of FASN using shRNAs or C75 decreased tumor growth, prolonged the overall survival of xenograft mice and decreased MVD in brain tumor sections. Moreover, inhibition of FASN blocked hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor A (VEGF-A) signaling and upregulated the anti-angiogenic isoform-VEGF165b.
CONCLUSION: Our results suggest that FASN plays a pivotal role in glioma neovascularization, and inhibition of FASN may be a potential target for anti-angiogenic therapy for glioma.

Yuan M, Zhu H, Xu J, et al.
Tumor-Derived CXCL1 Promotes Lung Cancer Growth via Recruitment of Tumor-Associated Neutrophils.
J Immunol Res. 2016; 2016:6530410 [PubMed] Free Access to Full Article Related Publications
Neutrophils have a traditional role in inflammatory process and act as the first line of defense against infections. Although their contribution to tumorigenesis and progression is still controversial, accumulating evidence recently has demonstrated that tumor-associated neutrophils (TANs) play a key role in multiple aspects of cancer biology. Here, we detected that chemokine CXCL1 was dramatically elevated in serum from 3LL tumor-bearing mice. In vitro, 3LL cells constitutively expressed and secreted higher level of CXCL1. Furthermore, knocking down CXCL1 expression in 3LL cells significantly hindered tumor growth by inhibiting recruitment of neutrophils from peripheral blood into tumor tissues. Additionally, tumor-infiltrated neutrophils expressed higher levels of MPO and Fas/FasL, which may be involved in TAN-mediated inhibition of CD4(+) and CD8(+) T cells. These results demonstrate that tumor-derived CXCL1 contributes to TANs infiltration in lung cancer which promotes tumor growth.

Cacan E
Histone Deacetylase-1-mediated Suppression of FAS in Chemoresistant Ovarian Cancer Cells.
Anticancer Res. 2016; 36(6):2819-26 [PubMed] Related Publications
BACKGROUND: Loss of FAS expression in ovarian cancer cells has recently been associated with resistance to chemotherapeutic drugs. However, the mechanism for suppression of FAS expression is unknown.
MATERIALS AND METHODS: The cell surface and transcript expressions of death receptors in parental chemosensitive (A2780) and their derivative chemoresistant (A2780-AD) ovarian cancer cells were determined by flow cytometry and quantitative real-time polymerase chain reaction, respectively. The epigenetic regulation of FAS promoters in both A2780 and A2780-AD ovarian epithelial cells were determined by chromatin immunoprecipitation assays.
CONCLUSION: This study demonstrated that expression of FAS is suppressed in A2780-AD cells compared to parental A2780 ovarian cells. No difference in DNA methylation was observed at FAS promoters between A2780-AD cells compared to parental cells. However, the level of acetylated histone H3 associated with FAS promoter in A2780-AD cells was significantly lower compared to parental cells, and there was a corresponding increase in histone deacetylase 1 (HDAC1) enzyme associated with the FAS promoter in resistant cells. Knockdown of HDAC1 expression, and pharmacological inhibition of HDAC enzymatic activity significantly increased FAS expression in resistant A2780-AD cells. These results suggest that epigenetic changes in histone modifications may contribute to the loss of FAS expression in chemoresistant ovarian cancer cells and that enhancement of FAS expression could increase tumor cell sensitivity to immune cells.

Sharma G, Rani I, Bhatnagar A, Agnihotri N
Apoptosis-Mediated Chemoprevention by Different Ratios of Fish Oil in Experimental Colon Carcinogenesis.
Cancer Invest. 2016; 34(5):220-30 [PubMed] Related Publications
Apoptosis plays an important role in prevention of colon cancer. In the present study, different ratios of fish oil and corn oil increased Fas expression in both phases and a decrease in FasL expression only in post initiation phase. Treatment with fish oil activated the intrinsic apoptotic pathway by increasing Bax expression and Cyt c release and decreasing Bcl-2 levels in both phases. This suggests that intrinsic pathway is upregulated by fish oil; however, Fas-FasL activity may be involved in inhibition of reversal of immune surveillance in tumor cells.

Dai B, Zhang P, Zhang Y, et al.
RNaseH2A is involved in human gliomagenesis through the regulation of cell proliferation and apoptosis.
Oncol Rep. 2016; 36(1):173-80 [PubMed] Related Publications
Mutations in the RNaseH2A gene are involved in Aicardi‑Goutieres syndrome, an autosomal recessive neurological dysfunction; however, studies assessing RNaseH2A in relation to glioma are scarce. This study aimed to assess the role of RNaseH2A in glioma and to unveil the underlying mechanisms. RNaseH2A was silenced in glioblastoma cell lines U87 and U251. Gene expression was assessed in the cells transfected with RNaseH2A shRNA or scramble shRNA by microarrays, validated by quantitative real time PCR. Protein expression was evaluated by western blot analysis. Cell proliferation was assessed by the MTT assay; cell cycle distribution and apoptosis were analyzed by flow cytometry. Finally, the effects of RNaseH2A on colony formation and tumorigenicity were assessed in vitro and in a mouse xenograft model, respectively. RNaseH2A was successively knocked down in U87 and U251 cells. Notably, RNaseH2A silencing resulted in impaired cell proliferation, with 70.7 and 57.8% reduction in the U87 and U251 cells, respectively, with the cell cycle being blocked in the G0/G1 phase in vitro. Meanwhile, clone formation was significantly reduced by RNaseH2A knockdown, which also increased cell apoptosis by approximately 4.5-fold. In nude mice, tumor size was significantly decreased after RNaseH2A knockdown: 219.29±246.43 vs. 1160.26±222.61 mm3 for the control group; similar findings were obtained for tumor weight (0.261±0.245 and 1.127±0.232 g) in the shRNA and control groups, respectively). In the microarray data, RNaseH2A was shown to modulate several signaling pathways responsible for cell proliferation and apoptosis, such as IL-6 and FAS pathways. RNaseH2A may be involved in human gliomagenesis, likely by regulating signaling pathways responsible for cell proliferation and apoptosis.

Zhang D, Li Y, Wang R, et al.
Inhibition of REST Suppresses Proliferation and Migration in Glioblastoma Cells.
Int J Mol Sci. 2016; 17(5) [PubMed] Free Access to Full Article Related Publications
Glioblastoma (GBM) is the most common primary brain tumor, with poor prognosis and a lack of effective therapeutic options. The aberrant expression of transcription factor REST (repressor element 1-silencing transcription factor) had been reported in different kinds of tumors. However, the function of REST and its mechanisms in GBM remain elusive. Here, REST expression was inhibited by siRNA silencing in U-87 and U-251 GBM cells. Then CCK-8 assay showed significantly decreased cell proliferation, and the inhibition of migration was verified by scratch wound healing assay and transwell assay. Using cell cycle analysis and Annexin V/PI straining assay, G1 phase cell cycle arrest was found to be a reason for the suppression of cell proliferation and migration upon REST silencing, while apoptosis was not affected by REST silencing. Further, the detection of REST-downstream genes involved in cytostasis and migration inhibition demonstrated that CCND1 and CCNE1 were reduced; CDK5R1, BBC3, EGR1, SLC25A4, PDCD7, MAPK11, MAPK12, FADD and DAXX were enhanced, among which BBC3 and DAXX were direct targets of REST, as verified by ChIP (chromatin immunoprecipitation) and Western blotting. These data suggested that REST is a master regulator that maintains GBM cells proliferation and migration, partly through regulating cell cycle by repressing downstream genes, which might represent a potential target for GBM therapy.

Kadam CY, Abhang SA
Apoptosis Markers in Breast Cancer Therapy.
Adv Clin Chem. 2016; 74:143-93 [PubMed] Related Publications
Cancer is a disease characterized by a very little apoptosis, ie, genetically programmed cell death. Aberrations in apoptotic pathways are central to tumorigenesis, tumor progression, and overall tumor growth and regression in response to chemotherapy. It is now increasingly accepted that chemotherapeutic drug efficacy is partially related to its ability to induce apoptosis. Apoptosis, therefore, represents not only a vital target in cancer therapy but also a unique biomarker opportunity that has thus far been largely unexploited. In response to therapy, tumor cells undergo apoptosis and release their cellular components in the circulation. As such, these materials may serve as biomarkers to assess response. Apoptosis markers in breast cancer include circulating soluble FasL, granzyme B, and cytochrome c that increase following chemotherapy. Unfortunately, there is a paucity of information in the literature with respect to this approach. As such, large-scale prospective studies are clearly needed to validate this approach and more fully elucidate clinical usefulness.

Chuang WL, Lin PY, Lin HC, Chen YL
The Apoptotic Effect of Ursolic Acid on SK-Hep-1 Cells is Regulated by the PI3K/Akt, p38 and JNK MAPK Signaling Pathways.
Molecules. 2016; 21(4):460 [PubMed] Related Publications
Ursolic acid (UA) is a pentacyclic triterpene acid that is present in a wide variety of medicinal herbs and edible plants. This study investigated the effect of UA on apoptosis and proliferation of hepatocellular carcinoma SK-Hep-1 cells. After treatment of SK-Hep-1 cells with different concentrations of UA, we observed that cell viability was reduced in a dose- and time-dependent manner. Furthermore, there was a dose-dependent increase in the percentage of cells in the sub-G1 and G2/M phases, with cells treated with 60 μM showing the highest percentages of cells in those phases. UA-induced chromatin condensation of nuclei was observed by using DAPI staining. The western blot results revealed that exposure to UA was associated with decreased expression of the anti-apoptotic proteins Mcl-1, Bcl-xL, Bcl-2, and TCTP and increased expression of apoptosis-related proteins TNF-α, Fas, FADD, Bax, cleaved caspase-3, caspase-8, caspase-9, and PARP. Immunocytochemistry staining showed that treatment with UA resulted in increased expression of caspase-3. Moreover, exposure to UA resulted in the inhibition of the PI3K/Akt and p38 MAPK signaling pathways. These findings suggest that UA inhibits the proliferation of SK-Hep-1 cells and induces apoptosis.

Mognol GP, Carneiro FR, Robbs BK, et al.
Cell cycle and apoptosis regulation by NFAT transcription factors: new roles for an old player.
Cell Death Dis. 2016; 7:e2199 [PubMed] Free Access to Full Article Related Publications
The NFAT (nuclear factor of activated T cells) family of transcription factors consists of four Ca(2+)-regulated members (NFAT1-NFAT4), which were first described in T lymphocytes. In addition to their well-documented role in T lymphocytes, where they control gene expression during cell activation and differentiation, NFAT proteins are also expressed in a wide range of cells and tissue types and regulate genes involved in cell cycle, apoptosis, angiogenesis and metastasis. The NFAT proteins share a highly conserved DNA-binding domain (DBD), which allows all NFAT members to bind to the same DNA sequence in enhancers or promoter regions. The same DNA-binding specificity suggests redundant roles for the NFAT proteins, which is true during the regulation of some genes such as IL-2 and p21. However, it has become increasingly clear that different NFAT proteins and even isoforms can have unique functions. In this review, we address the possible reasons for these distinct roles, particularly regarding N- and C-terminal transactivation regions (TADs) and the partner proteins that interact with these TADs. We also discuss the genes regulated by NFAT during cell cycle regulation and apoptosis and the role of NFAT during tumorigenesis.

Feng Y, Li Y, Zhang Y, et al.
Association of genetic variants with tumor HPV16 status and survival in squamous cell carcinoma of the oropharynx.
Oral Oncol. 2016; 56:78-83 [PubMed] Related Publications
OBJECTIVES: Genetic polymorphisms of genes in cell cycle, apoptosis, and inflammation/immune response pathways may control the mechanisms of HPV clearance and HPV escape of immune surveillance and thus may affect both tumor HPV16 status and possibly related outcomes of squamous cell carcinoma of the oropharynx (SCCOP) patients.
MATERIALS AND METHODS: We determined tumor HPV16 status and genotyped selected polymorphisms in key genes involved in cell cycle, apoptosis, and inflammation/immune response pathways in 401 incident SCCOP patients. Unconditional logistic regression models, Kaplan-Meier analysis, and Cox proportional hazards regression were used to evaluate associations and survival.
RESULTS: Compared to the corresponding common homozygous genotypes, the variant genotypes of genes in cell cycle (p53, p73, MDM2, p16), apoptosis (CASP8, and Fas), and inflammation/immune response pathways (IL1β and IL10) were significantly associated with HPV16-positive tumors among SCCOP patients. In HPV16-positive SCCOP patients only, compared to those with the corresponding common homozygous genotypes, patients with variant genotypes of p53 (119G>C), MDM2 (309T>G), p16 (580C>T), Fas (1377G>A), and IL1β (14T>C) had significantly better overall survival, and approximately 40-70% reduced or 5-fold increased risk of overall death, respectively, after adjustment for important prognostic confounders. Moreover, the combined adverse genotypes of 5 variants were also significantly associated with reduced risk of overall death of HPV16-positive SCCOP.
CONCLUSION: These results suggest that genetic polymorphisms in likely functional regions of the genes in these pathways may individually or, more likely, jointly affect individual susceptibility to HPV16 tumor status and constitute the confounding effect on HPV16-related clinical outcomes. Validation of our findings is warranted.

Yang X, Tietje AH, Yu X, Wei Y
Mouse interleukin-12/FasTI: A novel bi-functional fusion protein for cancer immuno/gene therapy.
Int J Oncol. 2016; 48(6):2381-6 [PubMed] Related Publications
Whereas cancer immunotherapy with cytokines in recent research was demonstrated effective in activating immune response against tumor cells, one major obstacle with the use of these cytokines is their severe side effects when delivered systemically at high doses. Another challenge is that advanced tumor cells often evade immunosurveillance of the immune system as well as of the Fas-mediated apoptosis by various mechanisms. We report the design and preliminary evaluation of the antitumor activity of a novel fusion protein-mIL-12/FasTI, consisting of mouse interleukin-12 and the transmembrane and intracellular domains of mouse Fas. The fusion construct (pmIL-12/FasTI) was transfected into mouse lung carcinoma cell line TC-1. Stable cell clones expressing the fusion protein were established as assayed by RT-PCR and immunohistochemistry. ELISA and cell proliferation analyses demonstrated that NK cells were effectively activated by the fusion protein with increased IFN-γ production and cytotoxicity. Enhanced caspase-3 activity of the clones when co-cultured with NK cells indicated that apoptosis was induced through Fas/FasL signaling pathway. The preliminary results suggest a synergized anticancer activity of the fusion protein. It may represent a promising therapeutic agent for cancer treatment.

Qin HD, Liao XY, Chen YB, et al.
Genomic Characterization of Esophageal Squamous Cell Carcinoma Reveals Critical Genes Underlying Tumorigenesis and Poor Prognosis.
Am J Hum Genet. 2016; 98(4):709-27 [PubMed] Free Access to Full Article Related Publications
The genetic mechanisms underlying the poor prognosis of esophageal squamous cell carcinoma (ESCC) are not well understood. Here, we report somatic mutations found in ESCC from sequencing 10 whole-genome and 57 whole-exome matched tumor-normal sample pairs. Among the identified genes, we characterized mutations in VANGL1 and showed that they accelerated cell growth in vitro. We also found that five other genes, including three coding genes (SHANK2, MYBL2, FADD) and two non-coding genes (miR-4707-5p, PCAT1), were involved in somatic copy-number alterations (SCNAs) or structural variants (SVs). A survival analysis based on the expression profiles of 321 individuals with ESCC indicated that these genes were significantly associated with poorer survival. Subsequently, we performed functional studies, which showed that miR-4707-5p and MYBL2 promoted proliferation and metastasis. Together, our results shed light on somatic mutations and genomic events that contribute to ESCC tumorigenesis and prognosis and might suggest therapeutic targets.

Cheng C, Jiao JT, Qian Y, et al.
Curcumin induces G2/M arrest and triggers apoptosis via FoxO1 signaling in U87 human glioma cells.
Mol Med Rep. 2016; 13(5):3763-70 [PubMed] Free Access to Full Article Related Publications
It has previously been demonstrated that curcumin possesses an antitumor activity, which is associated with its ability to induce G2/M cell cycle arrest and apoptosis. However the detailed underlying mechanisms remain unclear. The present study aimed to investigate the efficacy and underlying mechanism of curcumin‑induced cell cycle arrest and apoptosis in U87 human glioblastoma cells. By immunofluorescence staining, subcellular fractionation and western blotting, the present study demonstrated that curcumin was able to induce G2/M cell cycle arrest and apoptosis by increasing the expression levels of cyclin G2, cleaved caspase‑3 and Fas ligand (FasL), and decreasing the expression of cyclin‑dependent kinase 1 (CDK1). In addition, increased expression of forkhead box protein O1 (FoxO1) and decreased expression of phosphorylated (p)‑FoxO1 were detected in the curcumin‑treated U87 cells. Curcumin was also able to induce the translocation of FoxO1 from the cytoplasm to the nucleus. Furthermore, following knockdown of FoxO1 expression in curcumin‑treated U87 cells using FoxO1 small interfering RNA, the expression levels of cyclin G2, cleaved caspase‑3 and FasL were inhibited; however, the expression levels of CDK1 were not markedly altered. Notably, following knockdown of CDK1 expression under normal conditions, the total expression of FoxO1 was not affected; however, p‑FoxO1 expression was decreased and FoxO1 nuclear expression was increased. Furthermore, curcumin‑induced G2/M cell cycle arrest and apoptosis could be attenuated by FoxO1 knockdown. These results indicated that curcumin may induce G2/M cell cycle arrest and apoptosis in U87 cells by increasing FoxO1 expression. The present study identified a novel mechanism underlying the antitumor effects of curcumin, and may provide a theoretical basis for the application of curcumin in glioma treatment.

Cui Y, Lu P, Song G, et al.
Involvement of PI3K/Akt, ERK and p38 signaling pathways in emodin-mediated extrinsic and intrinsic human hepatoblastoma cell apoptosis.
Food Chem Toxicol. 2016; 92:26-37 [PubMed] Related Publications
As a natural anthraquinone derivative, 1,3,8-trihydroxy-6-methylanthraquinone, known as emodin, has recently been reported to possess potential chemopreventive capacity, but the underlying molecular mechanism of its hepatocyte toxicity remains poorly clarified. The present research indicated that emodin targeted HepG2 cells without being cytotoxic to primary human hepatocyte cells in comparison with chrysophanol and rhein. The anti-proliferative effect of emodin was ascribed to occurrence of apoptosis, which characterized by higher ethidium bromide signal, brighter DAPI fluorescence, cleavages of procaspase-3 and poly (ADP-ribose) polymerase as well as quantitative result from Annexin V-FITC/PI double staining. Furthermore, emodin improved Bax/Bcl-2 ratio, elicited disruption of mitochondrial membrane potential and promoted efflux of cytochrome c to cytosol, indicative of features of mitochondria-dependent apoptotic signals. Emodin concurrently led to activations of Fas, Fas-L, caspase-8 and tBid, which provoked death receptor apoptotic signals. Notably, activated tBid relayed the Fas apoptotic signal to the mitochondrial pathway. Besides, emodin effectively attenuated phosphorylations of Akt and ERK and promoted phosphorylation of p38. Inhibitions of PI3K/Akt and ERK and activation of p38 mediated emodin-induced apoptosis through modulating the mitochondrial pathway and/or death receptor pathway. Additionally, there was a cross-talk between PI3K/Akt and MAPKs pathways in emodin-induced apoptosis.

Fan H, Liang Y, Jiang B, et al.
Curcumin inhibits intracellular fatty acid synthase and induces apoptosis in human breast cancer MDA-MB-231 cells.
Oncol Rep. 2016; 35(5):2651-6 [PubMed] Related Publications
High levels of fatty acid synthase (FAS) expression have been found in many tumors, including prostate, breast, and ovarian cancers, and inhibition of FAS has been reported to obstruct tumor growth in vitro and in vivo. Curcumin is one of the major active ingredients of Curcuma longa, which has been proven to inhibit the growth of cancer cells. In the present study, we investigated the potential activity of curcumin as a FAS inhibitor for chemoprevention of breast cancer. As a result, curcumin induced human breast cancer MDA-MB-231 cell apoptosis with the half-inhibitory concentration value of 3.63 ± 0.26 µg/ml, and blocked FAS activity, expression and mRNA level in a dose-dependent manner. Curcumin also regulated B-cell lymphoma 2 (Bcl-2), Bax and p-Akt protein expression in MDA-MB-231 cells. Moreover, FAS knockdown showed similar effect as curcumin. All these results suggested that curcumin may induce cell apoptosis via inhibiting FAS.

Massari F, Ciccarese C, Santoni M, et al.
Metabolic phenotype of bladder cancer.
Cancer Treat Rev. 2016; 45:46-57 [PubMed] Related Publications
Metabolism of bladder cancer represents a key issue for cancer research. Several metabolic altered pathways are involved in bladder tumorigenesis, representing therefore interesting targets for therapy. Tumor cells, including urothelial cancer cells, rely on a peculiar shift to aerobic glycolysis-dependent metabolism (the Warburg-effect) as the main energy source to sustain their uncontrolled growth and proliferation. Therefore, the high glycolytic flux depends on the overexpression of glycolysis-related genes (SRC-3, glucose transporter type 1 [GLUT1], GLUT3, lactic dehydrogenase A [LDHA], LDHB, hexokinase 1 [HK1], HK2, pyruvate kinase type M [PKM], and hypoxia-inducible factor 1-alpha [HIF-1α]), resulting in an overproduction of pyruvate, alanine and lactate. Concurrently, bladder cancer metabolism displays an increased expression of genes favoring the pentose phosphate pathway (glucose-6-phosphate dehydrogenase [G6PD]) and the fatty-acid synthesis (fatty acid synthase [FASN]), along with a decrease of AMP-activated protein kinase (AMPK) and Krebs cycle activities. Moreover, the PTEN/PI3K/AKT/mTOR pathway, hyper-activated in bladder cancer, acts as central regulator of aerobic glycolysis, hence contributing to cancer metabolic switch and tumor cell proliferation. Besides glycolysis, glycogen metabolism pathway plays a robust role in bladder cancer development. In particular, the overexpression of GLUT-1, the loss of the tumor suppressor glycogen debranching enzyme amylo-α-1,6-glucosidase, 4-α-glucanotransferase (AGL), and the increased activity of the tumor promoter enzyme glycogen phosphorylase impair glycogen metabolism. An increase in glucose uptake, decrease in normal cellular glycogen storage, and overproduction of lactate are consequences of decreased oxidative phosphorylation and inability to reuse glucose into the pentose phosphate and de novo fatty acid synthesis pathways. Moreover, AGL loss determines augmented levels of the serine-to-glycine enzyme serine hydroxymethyltransferase-2 (SHMT2), resulting in an increased glycine and purine ring of nucleotides synthesis, thus supporting cells proliferation. A deep understanding of the metabolic phenotype of bladder cancer will provide novel opportunities for targeted therapeutic strategies.

Ren C, Ren T, Yang K, et al.
Inhibition of SOX2 induces cell apoptosis and G1/S arrest in Ewing's sarcoma through the PI3K/Akt pathway.
J Exp Clin Cancer Res. 2016; 35:44 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Ewing's sarcoma is an aggressive bone and soft tissue tumor with a high incidence in children and adolescents. Due to its high malignancy and poor prognosis, identification of novel biomarkers for intervention therapies is necessary to improve outcome. The EWS/FLI1 fusion gene is a characteristic of Ewing's sarcoma in most cases. Sex determining region Y-box 2 (SOX2) is a primary target of EWS/FLI1. It has been identified as an oncogene and linked to apoptotic resistance in several types of cancer. However, its role and regulatory mechanisms in Ewing's sarcoma are largely unknown.
METHODS: We systematically investigated the role of SOX2 in Ewing's sarcoma cell lines, human tissue samples and xenograft models. The expression of SOX2 was detected in Ewing's sarcoma samples by WB and IHC. siRNAs were used to knockdown EWS/FLI1 and SOX2 in A673 and RD-ES cell lines with the efficiencies tested by qRT-PCR and WB. The effect of SOX2 on cell cycle and apoptosis was determined by Flow cytometric and TUNEL assays. Akt overexpression was performed with plasmid. The protein expression of the corresponding factors was examined by WB analysis. Inhibition of SOX2 in vivo was performed by siRNA against SOX2 in xenograft models, and the protein expression of the regulators testified in vitro was examined in xenograft tumors by IHC and WB.
RESULTS: The results confirmed that SOX2 was highly expressed in Ewing's sarcoma and was the target of EWS/FLI1. SOX2 advanced Ewing's sarcoma cell survival and proliferation by regulating p21, p27 and cyclin-E to facilitate G1/S phase transition and mediating caspase-3, PARP via both extrinsic (Fas and caspase-8) and intrinsic (caspase-9, Bad, Bcl-2 and XIAP) apoptotic pathways to restrain cell apoptosis. Additionally, SOX2 regulated the cell-cycle progression and apoptosis via activation of the PI3K/Akt signaling pathway. The mechanisms were proved both in vitro and in vivo.
CONCLUSIONS: The results demonstrate that SOX2 played a central role in promoting Ewing's sarcoma cell proliferation in vitro and in vivo with the underlying mechanisms expounded. These findings suggest that SOX2 may serve as a potential biomarker for targeted intervention in Ewing's sarcoma.

Duan J, Sun L, Huang H, et al.
Overexpression of fatty acid synthase predicts a poor prognosis for human gastric cancer.
Mol Med Rep. 2016; 13(4):3027-35 [PubMed] Free Access to Full Article Related Publications
Fatty acid synthase (FASN), a lipogenic multi-enzyme complex, is reported to be overexpressed in various types of of tumor tissues and serves an important role in tumor development and progression. However, the expression of FASN and its possible role in gastric cancer (GC) remains to be defined. In the present study, FASN expression in a group sample of 167 GC tissues was detected by immunohistochemistry and its correlation with clinicopathological features was analyzed. By clinical analysis, it was identified that FASN overexpression was positively correlated with the overall survival [P=0.008; hazard ratio (HR), 4.412; 95% confidence interval (CI), 1.463‑13.305] and recurrence rate (P=0.014; HR, 1.705; 95% CI, 1.116‑2.606) in patients with GC. In addition, expression of the FASN protein in GC tissues was correlated with age (P=0.032), clinical stage (P<0.001), gastric wall invasion (P=0.014), lymph node metastasis (P<0.001) and distant metastasis (P<0.001), however not with gender (P>0.05). In addition, FASN was observed to be overexpressed in GC tissues at an mRNA and protein level, compared with the adjacent non-cancerous tissues (P<0.05). Taken together, it was suggested that FASN was closely associated with GC metastasis and survival, which further provided evidence that FASN may be a promising prognostic biomarker for patients with GC.

Mussazhanova Z, Akazawa Y, Matsuda K, et al.
Association between p53-binding protein 1 expression and genomic instability in oncocytic follicular adenoma of the thyroid.
Endocr J. 2016; 63(5):457-67 [PubMed] Related Publications
Oncocytic follicular adenomas (FAs) of the thyroid are neoplasms of follicular cell origin that are predominantly composed of large polygonal cells with eosinophilic and granular cytoplasm. However, the pathological characteristics of these tumors are largely unexplored. Both the initiation and progression of cancer can be caused by an accumulation of genetic mutations that can induce genomic instability. Thus, the aim of this study was to evaluate the extent of genomic instability in oncocytic FA. As the presence of p53-binding protein 1 (53BP1) in nuclear foci has been found to reflect DNA double-strand breaks that are triggered by various stresses, the immunofluorescence expression pattern of 53BP-1 was assessed in oncocytic and conventional FA. The association with the degree of DNA copy number aberration (CNA) was also evaluated using array-based comparative genomic hybridization. Data from this study demonstrated increased 53BP1 expression (i.e., "unstable" expression) in nuclear foci of oncocytic FA and a higher incidence of CNAs compared with conventional FA. There was also a particular focus on the amplification of chromosome 1p36 in oncocytic FA, which includes the locus for Tumor protein 73, a member of the p53 family implicated as a factor in the development of malignancies. Further evaluations revealed that unstable 53BP1 expression had a significant positive correlation with the levels of expression of Tumor protein 73. These data suggest a higher level of genomic instability in oncocytic FA compared with conventional FA, and a possible relationship between oncocytic FA and abnormal amplification of Tumor protein 73.

Wang H, Zhang X, Sun W, et al.
Activation of TIM1 induces colon cancer cell apoptosis via modulating Fas ligand expression.
Biochem Biophys Res Commun. 2016; 473(2):377-81 [PubMed] Related Publications
The pathogenesis of colon cancer is unclear. It is proposed that TIM1 has an association with human cancer. The present study aims to investigate the role of TIM1 activation in the inhibition of human colon cancer cells. In this study, human colon cancer cell line, HT29 and T84 cells were cultured. The expression of TIM1 was assessed by real time RT-PCR and Western blotting. The TIM1 on the cancer cells was activated in the culture by adding recombinant TIM4. The chromatin structure at the FasL promoter locus was assessed by chromatin immunoprecipitation. The apoptosis of the cancer cells was assessed by flow cytometry. The results showed that human colon cancer cell lines, HT29 cells and T84 cells, expressed TIM1. Activation of TIM1 by exposing the cells to TIM4 significantly increased the frequency of apoptotic colon cancer cells. The expression of FasL was increased in the cancer cells after treating by TIM4. Blocking Fas or FasL abolished the exposure to TIM4-induced T84 cell apoptosis. In conclusion, HT29 cells and T84 cells express TIM1; activation TIM1 can induce the cancer cell apoptosis. TIM1 may be a novel therapeutic target of colon cancer.

Trisdale SK, Schwab NM, Hou X, et al.
Molecular manipulation of keratin 8/18 intermediate filaments: modulators of FAS-mediated death signaling in human ovarian granulosa tumor cells.
J Ovarian Res. 2016; 9:8 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Granulosa cell tumors (GCT) are a rare ovarian neoplasm but prognosis is poor following recurrence. Keratin intermediate filaments expressed in these tumors are a diagnostic marker, yet paradoxically, may also constitute a target for therapeutic intervention. In the current study, we evaluated keratin 8/18 (K8/18) filament expression as a mechanism of resistance to apoptosis in GCT, specifically focusing on regulation of the cell surface death receptor, Fas (FAS).
METHODS: The GCT cell line, KGN, was transiently transfected with siRNA to KRT8 and KRT18 to reduce K8/18 filament expression. Expression of K8/18, FAS, and apoptotic proteins (PARP, cleaved PARP) were evaluated by fluorescence microscopy, flow cytometric analysis, and immunoblotting, respectively. The incidence of FAS-mediated apoptosis in KGN cells was measured by caspase 3/7 activity. All experiments were performed independently three to six times, using a fresh aliquot of KGN cells for each experiment. Quantitative data were analyzed by one- or two-way analysis of variance (ANOVA), followed by a Tukey's post-test for multiple comparisons; differences among means were considered statistically significant at P < 0.05.
RESULTS: Control cultures of KGN cells exhibited abundant K8/18 filament expression (~90 % of cells), and minimal expression of FAS (<25 % of cells). These cells were resistant to FAS-activating antibody (FasAb)-induced apoptosis, as determined by detection of cleaved PARP and measurement of caspase 3/7 activity. Conversely, siRNA-mediated knock-down of K8/18 filament expression enhanced FAS expression (> 70 % of cells) and facilitated FasAb-induced apoptosis, evident by increased caspase 3/7 activity (P < 0.05). Additional experiments revealed that inhibition of protein synthesis, but not MEK1/2 or PI3K signaling, also prompted FasAb-induced apoptosis.
CONCLUSIONS: The results demonstrated that K8/18 filaments provide resistance to apoptosis in GCT by impairing FAS expression. The abundance of keratin filaments in these cells and their role in apoptotic resistance provides a greater mechanistic understanding of ovarian tumorgenicity, specifically GCT, as well as a clinically-relevant target for potential therapeutic intervention.

Malki A, Mohsen M, Aziz H, et al.
New 3-Cyano-2-Substituted Pyridines Induce Apoptosis in MCF 7 Breast Cancer Cells.
Molecules. 2016; 21(2) [PubMed] Related Publications
The synthesis of new 3-cyano-2-substituted pyridines bearing various pharmacophores and functionalities at position 2 is described. The synthesized compounds were evaluated for their in vitro anti-cancer activities on five cancer cell lines using 5-FU as reference compound. The results revealed that the benzohydrazide derivative 9a induced growth inhibition in human breast cancer cell line MCF-7 with an IC50 value of 2 μM and it showed lower cytotoxicity on MCF-12a normal breast epithelial cells. Additionally, 9a induced apoptotic morphological changes and induced apoptosis in MCF-7 in a dose and time-dependent manner according to an enzyme linked immunosorbent apoptosis assay which is further confirmed by a TUNEL assay. Flow cytometric analysis indicated that 9a arrested MCF-7 cells in the G1 phase, which was further confirmed by increased expression of p21 and p27 and reduced expression of CDK2 and CDK4. Western blot data revealed significant upregulation of the expression of p53, Bax, caspase-3 and down-regulation of Bcl-2, Mdm-2 and Akt. Additionally, 9a increased the release of cytochrome c from mitochondria to cytoplasm which provokes the mitochondrial apoptotic pathway while it showed no significant change on the expression of the death receptor proteins procaspase-8, caspase-8 and FAS. Furthermore, 9a reduced the expression of phospho AKT and β-catenin in dose dependent manner while inhibiting the expression of migration-related genes such as matrix metalloproteinase (MMP)-9 and vascular endothelial growth factor (VEGF). Our findings suggest that compound 9a could be considered as a lead structure for further development of more potent apoptosis inducing agents with anti-metastatic activities.

Li Y, Zhang J, He J, et al.
MicroRNA-132 cause apoptosis of glioma cells through blockade of the SREBP-1c metabolic pathway related to SIRT1.
Biomed Pharmacother. 2016; 78:177-84 [PubMed] Related Publications
BACKGROUND: The inhibition role of miRNA (microRNA or miR) on cancer signaling pathways has been used to prospective cancer treatment. SIRT1 might promote tumorigenesis in human glioma.
METHODS: Here, we investigated whether miR-132 regulate the expression of SIRT1 and its downstream SREBP (Sterol regulatory element-binding protein)-lipogenesis-cholesterogenesis metabolic pathway in human glioma cells. Furthermore, we studied the effect on biology function of glioma cell induced by miR-132.
RESULTS: MiR-132 inhibited SIRT1 and SREBP-1c expression and downregulated their targeted genes, including HMGCR and FASN. MiR-132 suppressed the cell growth, tumorigenicity, the invasion of glioma cells and migration as well as promoted their apoptosis. The pathways associated with cancer progression and tumorigenicity, and induce glioma cell apoptosis has been inhibited by miR-132 involving in a caspase-dependent apoptotic mechanism.
CONCLUSIONS: The recovery of miR-132 resulted in caspase-dependent apoptotic death in glioma cells. MiR-132 that was newly discovered represents a newly targeting mechanism in treatment for glioma.

Huang FJ, Zhou XY, Ye L, et al.
Follicular thyroid carcinoma but not adenoma recruits tumor-associated macrophages by releasing CCL15.
BMC Cancer. 2016; 16:98 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: The differential diagnosis of follicular thyroid carcinoma (FTC) and follicular adenoma (FA) before surgery is a clinical challenge. Many efforts have been made but most focusing on tumor cells, while the roles of tumor associated macrophages (TAMs) remained unclear in FTC. Here we analyzed the differences between TAMs in FTC and those in FA.
METHODS: We first analyzed the density of TAMs by CD68 immunostaining in 59 histologically confirmed FTCs and 47 FAs. Cytokines produced by FTC and FA were profiled using antibody array, and validated by quantitative PCR. Chemotaxis of monocyte THP-1 was induced by condition medium of FTC cell lines (FTC133 and WRO82-1) with and without anti-CCL15 neutralizing antibody. Finally, we analyzed CCL15 protein level in FTC and FA by immunohistochemistry.
RESULTS: The average density of CD68(+) cells was 9.5 ± 5.4/field in FTC, significantly higher than that in FA (4.9 ± 3.4/field, p < 0.001). Subsequently profiling showed that CCL15 was the most abundant chemokine in FTC compared with FA. CCL15 mRNA in FTC was 51.4-folds of that in FA. CM of FTC cell lines induced THP-1 cell chemotaxis by 33 ~ 77%, and anti-CCL15 neutralizing antibody reduced THP-1 cell migration in a dose-dependent manner. Moreover, we observed positive CCL15 immunostaining in 67.8% of FTCs compared with 23.4% of FAs.
CONCLUSION: Our study suggested FTC might induce TAMs infiltration by producing CCL15. Measurement of TAMs and CCL15 in follicular thyroid lesions may be applied clinically to differentiate FTC from FA pre-operation.

Brown AS, Kong SW, Kohane IS, Patel CJ
ksRepo: a generalized platform for computational drug repositioning.
BMC Bioinformatics. 2016; 17:78 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Repositioning approved drug and small molecules in novel therapeutic areas is of key interest to the pharmaceutical industry. A number of promising computational techniques have been developed to aid in repositioning, however, the majority of available methodologies require highly specific data inputs that preclude the use of many datasets and databases. There is a clear unmet need for a generalized methodology that enables the integration of multiple types of both gene expression data and database schema.
RESULTS: ksRepo eliminates the need for a single microarray platform as input and allows for the use of a variety of drug and chemical exposure databases. We tested ksRepo's performance on a set of five prostate cancer datasets using the Comparative Toxicogenomics Database (CTD) as our database of gene-compound interactions. ksRepo successfully predicted significance for five frontline prostate cancer therapies, representing a significant enrichment from over 7000 CTD compounds, and achieved specificity similar to other repositioning methods.
CONCLUSIONS: We present ksRepo, which enables investigators to use any data inputs for computational drug repositioning. ksRepo is implemented in a series of four functions in the R statistical environment under a BSD3 license. Source code is freely available at http://github.com/adam-sam-brown/ksRepo. A vignette is provided to aid users in performing ksRepo analysis.

Sun Y, Yu W, Sturgis EM, et al.
Site disparities in apoptotic variants as predictors of risk for second primary malignancy in patients with squamous cell carcinoma of the head and neck.
BMC Cancer. 2016; 16:70 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: FAS/FASL promoter variants are considered in altering transcriptional activity of those genes and consequently alter regulation of cell death. However, no studies have investigated whether tumor sites contribute to the association between FAS/FASL polymorphisms and risk for second primary malignancy (SPM).
METHOD: In this study, FAS670 A > G, FAS1377 G > A, FASL124 A > G, and FASL844C > T polymorphisms were genotyped in 752 OPC and 777 non-OPC patients. Both univariate and multivariable cox proportional hazard models were used to assess the associations.
RESULTS: The univariate and multivariable analyses showed that patients with index OPC and FASL844 CT/TT genotype had significantly increased risk of SPM (cHR, 2.5; 95% CI, 1.1-5.8, P = 0.043 and aHR, 2.7; 95% CI, 1.2-6.0, P = 0.032) compared with those with FASL844 CC genotype as the reference group, while index non-OPC patients with FAS670 AG/GG and FasL844 CT/TT genotypes had significantly increased risk of SPM (cHR, 2.2 and 1.8; 95% CI, 1.2-5.7 and 1.1-3.2; and P = 0.04 and 0.041, respectively and aHR, 2.4 and 1.7; 95% CI, 1.1-5.1 and 1.0-3.0; and P = 0.043 and 0.049, respectively) compared with their corresponding AA and CC genotypes . Moreover, patients carrying more FAS/FASL variants significantly increased risk of SPM among index non-OPC patients. The stratified analysis showed that smoking status differently modified the associations between FAS/FASL polymorphisms and risk of SPM among index non-OPC from OPC patients.
CONCLUSION: These results suggested that FAS/FASL polymorphisms might significantly modify SPM risk among patients with SCCHN in a tumor site-specific manner.

Devor EJ, Schickling BM, Reyes HD, et al.
Cullin-5, a ubiquitin ligase scaffold protein, is significantly underexpressed in endometrial adenocarcinomas and is a target of miR-182.
Oncol Rep. 2016; 35(4):2461-5 [PubMed] Free Access to Full Article Related Publications
Altered expression of cullin-5 (CUL5), a member of the cullin-RING E3 ubiquitin ligase family, has been implicated in a number of types of cancers including breast, cervical and hepatocellular cancers. In the present study, we found that CUL5 expression was significantly decreased in both endometrioid and serous endometrial adenocarcinomas with the more aggressive serous type displaying a higher reduction (-4.3-fold) than the less aggressive endometrioid type (-2.9-fold). Overexpression of CUL5 mRNA and protein in Ishikawa H endometrial cancer cells resulted in decreased cell proliferation and in a reduction in CUL5-RING E3 ligase downstream clients JAK2 and FAS-L. Finally, we demonstrated for the first time that CUL5 is a direct target of miR-182 that we previously showed to be significantly overexpressed in endometrial adenocarcinomas and we provided evidence that increased miR-182 expression is, at least in part, a result of demethylation of its upstream promoter. These data suggest a cascade in which miR-182 expression is epigenetically increased leading to decreased CUL5 expression and increased cellular proliferation. The final step in the cascade may be operating through a decrease in ubiquitination of pro-growth CUL5 ubiquitin ligase clients. This cascade offers a series of potential interventional steps involving epigenetic modification, miRNA and/or gene targeting and ubiquitination.

Disclaimer: This site is for educational purposes only; it can not be used in diagnosis or treatment.

Cite this page: Cotterill SJ. FASN, Cancer Genetics Web: http://www.cancer-genetics.org/FASN.htm Accessed:

Creative Commons License
This page in Cancer Genetics Web by Simon Cotterill is licensed under a Creative Commons Attribution-ShareAlike 4.0 International License.
Note: content of abstracts copyright of respective publishers - seek permission where appropriate.

 [Home]    Page last revised: 11 March, 2017     Cancer Genetics Web, Established 1999