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

Abstract

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.

Single-cell transcriptomics of human islet ontogeny defines the molecular basis of β-cell dedifferentiation in T2D

“…Additionally, NHP2 and RPS19BP1 , both involved in ribosome biosynthesis, are upregulated in a large proportion of T2D β-cells as is the Alzheimer's disease risk gene PLD3 , a lysosomal enzyme associated with amyloid formation [ 69 ], which could be relevant to the characteristic amyloid formation in diabetic islets [ 70 ]. Finally, SRA1 , a steroid receptor transcription coactivator and long non-coding RNA, and FAT1 , a member of the cadherin superfamily involved in adhesion and signalling [ 71 ] are re-activated to newborn state expression levels (5.8 and 4.9 fold higher in newborn and T2D than ND adult, respectively) ( Figure S2A ). The function of most of these age-regulated genes in β-cells and the contribution of their dysregulation to dysfunction in the diabetic state has yet to be determined.…”

Exploring the Mechanism of Scutellaria baicalensis Georgi Efficacy against Oral Squamous Cell Carcinoma Based on Network Pharmacology and Molecular Docking Analysis

“…Nitrogen acquisition and utilization have essential effects on cancer and immunity [62]. Oxidative stress and its induced oxidative damage are important factors in OSCC formation and development [63,64], which provided another insight into the mechanism of SBG in the treatment of OSCC.…”

Analysis of cellular senescence in gingival tissues and gingival fibroblast cultures

“…Normal human gingival broblasts (HGFs #PCS-201-018, American Type Culture Collection, Manassas, VA) were cultured in DMEM (#D6429, Sigma-Aldrich, St. Louis, MO) with 10% FBS at 37 °C in a humidi ed atmosphere of 5% CO2. 11 The cells were cultured until 70% con uence on 100-mm diameter culture dishes and then transferred to 6-well at-bottom culture plates to perform the following experiments.…”