FAT Atypical Cadherin 1 Research Articles

Role of FAT1 in health and disease (Review)

FAT atypical cadherin 1 (FAT1), which encodes a protocadherin, is one of the most frequently mutated genes in human cancer. Over the past 20 years, the role of FAT1 in tissue growth and in the development of diseases has been extensively studied. There is definitive evidence that FAT1 serves a substantial role in the maintenance of organs and development, and its expression appears to be tissue-specific. FAT1 activates a variety of signaling pathways through protein-protein interactions, including the Wnt/β-catenin, Hippo and MAPK/ERK signaling pathways, which affect cell proliferation, migration and invasion. Abnormal FAT1 expression may lead to the development of tumors and may affect prognosis. Therefore, FAT1 may have potential in tumor therapy. The structural and functional changes mediated by FAT1, its tissue distribution and changes in FAT1 expression in human diseases are described in the present review, which provides further insight for understanding the role of FAT1 in development and disease.

Sulforaphane suppresses the viability and metastasis, and promotes the apoptosis of bladder cancercells by inhibiting the expression of FAT‑1.

FAT atypical cadherin 1 (FAT1) regulates complex mechanisms for the promotion of oncogenesis or the suppression of malignancies. Sulforaphane (SFN) has antioxidant and anti-tumor activities. The present study investigated the roles of SFN and FAT1 in bladder cancer (BC). The expression of FAT1 in BC cell lines and tissues was measured by western blot analysis and reverse transcription-quantitative PCR (RT-qPCR). The association between FAT1 expression and the 5-year survival rate of patients with BC was evaluated. The viability of and FAT1 expression in T24 and SW780 cells exposed to various concentrations of SFN were detected by MTT assay, and western blot analysis and RT-qPCR, respectively. Furthermore, the viability, migration, invasion and apoptosis of and FAT1 expression in BC cells subjected to FAT1 overexpression or knockdown, and with or without SFN stimulation, were examined. The results revealed that FAT1 expression in BC cells and tissues was increased, and patients with a high FAT-1 expression had a shorter 5-year survival time than those with a low FAT-1 expression. BC cell viability and FAT1 expression were suppressed by SFN in a concentration-dependent manner. The knockdown of FAT1 inhibited the viability, migration and invasion, and promoted the apoptosis of BC cells, whereas the overexpression of FAT1 produced opposite effects. In addition, cells exposed to SFN exhibited a reduced viability, migration, invasion and an increased apoptosis, effects which were promoted by FAT1 knockdown; however, the overexpression of FAT1 blocked the above-mentioned effects of SFN on the cells. On the whole, the present study demonstrates that SFN suppresses the progression of BC by inhibiting the expression of FAT-1; thus, SFN may be used as a potential drug for the treatment of BC.

Polymorphisms and association of FAT1 gene with wool quality traits in Chinese Merino sheep

FAT atypical cadherin 1 (FAT1) is a member of the atypical cadherin superfamily and is involved in the planar cell polarity signalling pathway which regulates hair follicle morphogenesis, cycling, and orientation. The purpose of this study was to investigate the sheep FAT1 gene expression, polymorphisms and its association with wool quality traits in Chinese Merino sheep. Quantitative real-time PCR analysis showed that the FAT1 mRNA was differentially expressed in the adult skin of Chinese Merino and Kazak sheep. Seven SNPs (termed SNPs 1–7) were identified in exon 2 of sheep FAT1 gene by Sanger sequencing. SNPs 2 and 7 (novel SNPs) were significantly associated with wool crimp (P < 0.05). SNPs 4 and 5 (rs161528993 and rs161528992) were significantly associated with wool fibre length (P < 0.05). SNP 7 was highly significantly associated with average wool fibre diameter (P < 0.01). Similarly, FAT1 haplotypes were significantly associated with wool crimp (P < 0.05), and the haplotypes H1–H3 and H5 were significantly associated with higher wool crimp (P < 0.05). Bioinformatics analysis showed that the wool quality trait-associated SNPs (SNPs 2, 4, 5 and 7) might affect the pre-mRNA splicing by creating or abolishing the binding sites for serine/arginine-rich proteins, and in addition, SNPs 2 and 4 might alter the FAT1 mRNA secondary structure. Our results suggest that FAT1 influences wool quality traits and its SNPs 2, 4, 5 and 7 might be useful markers for marker-assisted selection and sheep breeding.

IDH1-R132H Suppresses Glioblastoma Malignancy through FAT1-ROS-HIF-1α Signaling.

Glioblastoma (GBM) is one of the most deadly primary malignant brain tumors in adults. R132H mutation of isocitrate dehydrogenase 1 (IDH1) predicts a better prognosis of GBM. IDH1-R132H is associated with increased hypoxia-inducible factor-1α (HIF-1α) expression in GBM tumors. However, the molecular mechanism underlying IDH1-R132H-HIF-1α signaling in GBM is still unclear. We aimed to investigate the molecular pathway of IDH1-R132H-HIF-1α in the regulation of GBM. U87 and U251 GBM cells and xenograft tumor mice were used. We found that overexpression of IDH1-R132H decreased cell proliferation, increased apoptosis, decreased migration and invasion, enhanced temozolomide (TMZ)-induced cytotoxicity, and reduced tumor growth in xenograft mice. Overexpression of IDH1-R132H increased the expression of HIF-1α and downregulation of HIF-1α suppressed IDH1-R132H-induced effect on GBM. Reactive oxygen species (ROS) level was increased by IDH1-R132H over expression and the use of antioxidant inhibited IDH1-R132H-induced increase of HIF-1α expression. FAT Atypical Cadherin 1 (FAT1) expression was increased by IDH1-R132H over expression. Knockdown of FAT1 blocked IDH1-R132H-induced reduction of tumor growth in xenograft mice. Down regulation of FAT1 decreased HIF-1α expression and inhibited IDH1-R132H-induced increase of ROS level. Our findings provide new insights into IDH1-R132H-regulated downstream signaling in GBM and highlight the importance of IDH1-R132H-FAT1-ROS-HIF-1α signaling pathway in potential therapeutic intervention of GBM.

Hippo Pathway and YAP Signaling Alterations in Squamous Cancer of the Head and Neck.

Head and neck cancer affects the upper aerodigestive tract and is the sixth leading cancer worldwide by incidence and the seventh by cause of death. Despite significant advances in surgery and chemotherapy, molecularly targeted therapeutic options for this type of cancer are scarce and long term survival rates remain low. Recently, comprehensive genomic studies have highlighted the most commonly altered genes and signaling pathways in this cancer. The Hippo-YAP pathway has been identified as a key oncogenic pathway in multiple tumors. Expression of genes controlled by the Hippo downstream transcriptional coactivators YAP (Yes-associated protein 1) and TAZ (WWTR1, WW domain containing transcription regulator 1) is widely deregulated in human cancer including head and neck squamous cell carcinoma (HNSCC). Interestingly, YAP/TAZ signaling might not be as essential for the normal homeostasis of adult tissues as for oncogenic growth, altogether making the pathway an amenable therapeutic target in cancer. Recent advances in the role of Hippo-YAP pathway in HNSCC have provided evidence that genetic alterations frequent in this type of cancer such as PIK3CA (phosphatidylinositide 3-kinase catalytic subunit alpha) overexpression or FAT1 (FAT atypical cadherin 1) functional loss can result in YAP activation. We discuss current therapeutic options targeting this pathway which are currently in use for other tumor types.

Targeting FAT1 Inhibits Carcinogenesis, Induces Oxidative Stress and Enhances Cisplatin Sensitivity through Deregulation of LRP5/WNT2/GSS Signaling Axis in Oral Squamous Cell Carcinoma.

FAT atypical cadherin 1 (FAT1) regulates cell-cell adhesion and extracellular matrix architecture, while acting as tumor suppressor or oncogene, context-dependently. Despite implication of FAT1 in several malignancies, its role in oral squamous cell carcinoma (OSCC) remains unclear. Herein, we document the driver-oncogene role of FAT1, and its mediation of cell-death evasion, proliferation, oncogenicity, and chemoresistance in OSCC. In-silica analyses indicate FAT1 mutations are frequent and drive head-neck SCC, with enhanced expression defining high-risk population and poor prognosis. We demonstrated aberrant FAT1 mRNA and protein expression in OSCC compared with non-cancer tissues, whereas loss-of-FAT1-function attenuates human primary SAS and metastatic HSC-3 OSCC cell viability, without affecting normal primary human gingival fibroblast cells. shFAT1 suppressed PCNA and upregulated BAX/BCL2 ratio in SAS and HSC-3 cells. Moreover, compared with wild-type cells, shFAT1 concomitantly impaired HSC-3 cell migration, invasion, and clonogenicity. Interestingly, while over-expressed FAT1 characterized cisplatin-resistance (CispR), shFAT1 synchronously re-sensitized CispR cells to cisplatin, enhanced glutathione (GSH)/GSH synthetase (GSS)-mediated oxidative stress and deregulated LRP5/WNT2 signaling. Concisely, FAT1 is an actionable driver-oncogene in OSCC and targeting FAT1 in patients with erstwhile cisplatin-resistant OSCC is therapeutically promising.

IDENTIFICATION OF Q2933P MUTATION IN FAT1 GENE IN A PATIENT WITH INTECLLECTUAL DISABILITY FROM DIOXIN VICTIM’S VIETNAM FAMILY

Dioxins are a group of chemicals known as highly toxic environmental persistent organic pollutants (POPs). Numerous dioxin-like compounds have been identified, such as polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), polychlorinated/polybrominated biphenyls (PCBs/PBBs), and 1,4-dioxin. The singular term dioxin refers to the most toxic compound, 2,3,7,8-tetrachlorodibenzodioxin (2,3,7,8-TCDD). Dioxin pollution caused by chemical warfare has been causing serious consequences to the ecological environment and especially to the health of Vietnamese people. In particular, dioxin was demonstrated to be the cause of many diseases, including diseases related to the nervous system of which intellectual disability is one of the 17 diseases have been recognized by Vietnam. Deformities, birth defects, intellectual disability have been detected in F1 and F2 generations of the exposed victims. Dioxin may cause changes in the whole genome / genome expression (exome), or the structure and function of the gene that leads to pathogenesis in the exposed people and the genetic changes can be passed on to the next generations. In the present study, the Whole Exome Sequencing (WES) method was used to analyze and identify genetic variants related to the intellectual disability in a dioxin exposed victim’s family in Vietnam. The screening results revealed that a Gln2933Pro heterozygous mutant in the FAT1 (Fat atypical cadherin 1) gene of the patient was inherited from the patient’s father whose high blood concentration of dioxin, as well as illustrated the changes in the protein structure. In addition to the important scientific implications, this result might be essential for providing counseling for families who are the dioxin victims.

Fat atypical cadherin 1 regulating invasion by targeting hypoxia inducible factor-1α in high grade glioma

Objective To investigate the action mechanism of fat atypical cadherin 1 (FAT1) regulating invasion by targeting hypoxia inducible factor-1α (HIF-1α) in high grade glioma under hypoxia. Methods The expression levels of FAT1 and HIF-1α in 48 cases of grade Ⅲ-Ⅳ glioma athological tissue samples in our hospital were detected by real-time fluorescent quantitative polymerase chain reaction (FQ-PCR). The relationship between the expression of FAT1 and HIF-1α was analyzed. The expression of FAT1 and HIF-1α in human glioma cells U87MG and GOS3 under the condition of normal oxygen (20% O2) and hypoxia (1% O2) was detected by FQ-PCR. FAT1 small interfering RNA (siRNA), HIF-1α siRNA and control siRNA were transfected into U87MG and GOS3 cell lines respectively by Lipofectamine 2000. The expression of FAT1 and HIF-1 under the normal oxygen and hypoxia conditions was detected. The invasive abilities of U87MG and GOS3 glioma cells were examined by cell chamber technique. Results The relative expression levels of FAT1 and HIF-1α in 48 cases of pathological tissues of patients with grade Ⅲ-Ⅳ glioma were 4.07 (0.72, 13.42) and 0.94 (0.29, 3.49) respectively. Spearman analysis showed that there was significant correlation between the relative expression levels of FAT1 and HIF-1α (r=0.835, P=0.000). The normal oxygen concentration in GOS3 cell lines FAT1 (0.29±0.03) and HIF-1α (0.34±0.09) relative expression levels were significantly lower than that of U87MG cells (1.08±0.15, 1.00±0.12; t=8.945, 7.621; P=0.010, 0.002); hypoxia condition, U87MG and GOS3 cell lines FAT1 and HIF-1α relative expression levels were significantly higher than the normal oxygen concentration (t=17.994, 8.920, 14.047, 4.037; P=0.000, 0.001, 0.004, 0.016); U87MG cells under hypoxic conditions FAT1 (4.38±0.28) and HIF-1α (2.76±0.32) relative expression levels were significantly higher than that of GOS3 cell line (1.69±0.17, 0.83±0.19; t=14.224, 8.982; P=0.000, 0.001). After transfection of FAT1 siRNA, FAT1 (0.17±0.06, 0.16±0.03, 0.16±0.03, 0.18±0.03) and HIF-1α (0.18±0.03, 0.17±0.04, 0.15±0.04, 0.21±0.02) relative expression levels of U87MG and GOS3 cells in the normal oxygen and hypoxia were significantly decreased (t=7.577, 7.793, 7.793, 7.783, 9.285, 9.260, 9.484, 9.042; P=0.002, 0.013, 0.013, 0.014, 0.009, 0.007, 0.007, 0.011). After transfection of HIF-1α siRNA, FAT1 (0.16±0.04, 0.28±0.03) relative expression levels in the normal oxygen and HIF-1α (0.15±0.03, 0.16±0.02, 0.15±0.03, 0.17±0.02) relative expression levels of U87MG and GOS3 cells in normal oxygen and hypoxia conditions were significantly decreased (t=7.890, 6.834, 9.624, 9.614, 9.624, 9.500; P=0.012, 0.018, 0.008, 0.009, 0.008, 0.010); but the level under hypoxic conditions relative expression of FAT1 (4.27±0.41, 2.72±0.25) were significantly higher than that in normal oxygen conditions (t=12.649, 9.671; P=0.000, 0.001). Under hypoxic conditions, the invasion cell quantity of U87MG cells transfected with FAT1 siRNA and HIF-1α siRNA [(23.2±4.2) and (21.5±3.1) cells] were lower than those of normal oxygen conditions [(57.6±8.1) and (58.7±7.6) cells; t=6.530, 7.850; P=0.003, 0.001]. Conclusion The expression of FAT1 and HIF-1 in high grade gliomas is strongly correlated, and the expression is high under the hypoxia condition. FAT1 can promote the invasion of glioma cells by targeting HIF-1α. Key words: Glioma; Fat atypical cadherin; Hypoxia inducible factor-1α; Invasion

FAT1 inhibits cell migration and invasion by affecting cellular mechanical properties in esophageal squamous cell carcinoma

FAT atypical cadherin 1 (FAT1) belongs to the cadherin superfamily and has been reported to regulate cell-cell adhesion and other cell behaviors, suggesting its pivotal roles in human cancers. We previously identified FAT1 as one of the significant mutant genes in esophageal squamous cell carcinoma (ESCC). In the present study, the knockdown of FAT1 expression in YSE2 and Colo680N cell lines was carried out by lentivirus, and we found that knockdown of FAT1 led to acceleration of cell migration and invasion. Furthermore, we detected the cell adhesive force and cell elasticity force by atomic force microscopy (AFM) and found that the suppression of endogenous expression of FAT1 led to a decrease in the cell adhesive force and increase in the cell elasticity force compared with the control groups. In conclusion, our study demonstrated that FAT1 altered cellular mechanical properties leading to deregulation of cell migration and invasion of ESCC, which may be a novel target for ESCC therapy.

Novel Genetic Associations Between Lung Cancer and Indoor Radon Exposure.

BackgroundLung cancer is the leading cause of cancer-related death worldwide, for which smoking is considered as the primary risk factor. The present study was conducted to determine whether genetic alterations induced by radon exposure are associated with the susceptible risk of lung cancer in never smokers.MethodsTo accurately identify mutations within individual tumors, next generation sequencing was conduct for 19 pairs of lung cancer tissue. The associations of germline and somatic variations with radon exposure were visualized using OncoPrint and heatmap graphs. Bioinformatic analysis was performed using various tools.ResultsAlterations in several genes were implicated in lung cancer resulting from exposure to radon indoors, namely those in epidermal growth factor receptor (EGFR), tumor protein p53 (TP53), NK2 homeobox 1 (NKX2.1), phosphatase and tensin homolog (PTEN), chromodomain helicase DNA binding protein 7 (CHD7), discoidin domain receptor tyrosine kinase 2 (DDR2), lysine methyltransferase 2C (MLL3), chromodomain helicase DNA binding protein 5 (CHD5), FAT atypical cadherin 1 (FAT1), and dual specificity phosphatase 27 (putative) (DUSP27).ConclusionsWhile these genes might regulate the carcinogenic pathways of radioactivity, further analysis is needed to determine whether the genes are indeed completely responsible for causing lung cancer in never smokers exposed to residential radon.

Impact of polyunsaturated and saturated fat overfeeding on the DNA-methylation pattern in human adipose tissue: a randomized controlled trial1–3

Background: Dietary fat composition can affect ectopic lipid accumulation and, thereby, insulin resistance. Diets that are high in saturated fatty acids (SFAs) or polyunsaturated fatty acids (PUFAs) have different metabolic responses.Objective: We investigated whether the epigenome of human adipose tissue is affected differently by dietary fat composition and general overfeeding in a randomized trial.Design: We studied the effects of 7 wk of excessive SFA (n = 17) or PUFA (n = 14) intake (+750 kcal/d) on the DNA methylation of ~450,000 sites in human subcutaneous adipose tissue. Both diets resulted in similar body weight increases. We also combined the data from the 2 groups to examine the overall effect of overfeeding on the DNA methylation in adipose tissue.Results: The DNA methylation of 4875 Cytosine-phosphate-guanine (CpG) sites was affected differently between the 2 diets. Furthermore, both the SFA and PUFA diets increased the mean degree of DNA methylation in adipose tissue, particularly in promoter regions. However, although the mean methylation was changed in 1797 genes [e.g., alpha-ketoglutarate dependent dioxygenase (FTO), interleukin 6 (IL6), insulin receptor (INSR), neuronal growth regulator 1 (NEGR1), and proopiomelanocortin (POMC)] by PUFAs, only 125 genes [e.g., adiponectin, C1Q and collagen domain containing (ADIPOQ)] were changed by SFA overfeeding. In addition, the SFA diet significantly altered the expression of 28 transcripts [e.g., acyl-CoA oxidase 1 (ACOX1) and FAT atypical cadherin 1 (FAT1)], whereas the PUFA diet did not significantly affect gene expression. When the data from the 2 diet groups were combined, the mean methylation of 1444 genes, including fatty acid binding protein 1 (FABP1), fatty acid binding protein 2 (FABP2), melanocortin 2 receptor (MC2R), MC3R, PPARG coactivator 1 α (PPARGC1A), and tumor necrosis factor (TNF), was changed in adipose tissue by overfeeding. Moreover, the baseline DNA methylation of 12 CpG sites that was annotated to 9 genes [e.g., mitogen-activated protein kinase 7 (MAPK7), melanin concentrating hormone receptor 1 (MCHR1), and splicing factor SWAP homolog (SFRS8)] was associated with the degree of weight increase in response to extra energy intake.Conclusions: SFA overfeeding and PUFA overfeeding induce distinct epigenetic changes in human adipose tissue. In addition, we present data that suggest that baseline DNA methylation can predict weight increase in response to overfeeding in humans. This trial was registered at http://clinicaltrials.gov as NCT01427140.

Association between FAT1 mutation and overall survival in patients with human papillomavirus-negative head and neck squamous cell carcinoma.

BackgroundThe purpose of this study was to characterize the mutation profile of FAT atypical cadherin 1 (FAT1) and determine the prognostic significance of FAT1 mutation for overall survival in patients with human papillomavirus (HPV)‐negative head and neck squamous cell carcinoma (HNSCC).MethodsData were downloaded from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) data portals and used as discovery and validation sets. FAT1 mutational status was determined in 234 and 37 patients with HPV‐negative HNSCC, respectively, and overall survival analysis was performed. For comparison, HPV‐positive patients were also analyzed for overall survival.ResultsMost of the identified nonsynonymous somatic FAT1 mutations were loss‐of‐function mutations. FAT1 mutation was significantly associated with better overall survival in HPV‐negative patients from both the TCGA cohort (p = .026) and the ICGC cohort (p = .047), but not in HPV‐positive patients.Conclusion FAT1 mutational status is a strong independent prognostic factor in patients with HPV‐negative HNSCC. © 2016 The Authors Head & Neck Published by Wiley Periodicals, Inc. Head Neck 38: E2021–E2029, 2016