Targeting FAT1 inhibits carcinogenesis, induces oxidative stress and enhances cisplatin sensitivity through deregulation of LRP5/WNT2/GSS signaling axis in oral squamous cell carcinoma

Tung Nien Hsu, Chih Ming Huang, Chin Sheng Huang, Mao Suan Huang, Chi Tai Yeh, Tsu Yi Chao, Oluwaseun Adebayo Bamodu

Research output: Contribution to journalArticlepeer-review

25 Citations (Scopus)

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.

Original languageEnglish
Article number1883
JournalCancers
Volume11
Issue number12
DOIs
Publication statusPublished - Dec 2019

Keywords

  • Atypical cadherin
  • Chemoresistance
  • Cisplatin
  • FAT1
  • GSH
  • GSS
  • LRP5
  • Oncogene
  • OSCC
  • Oxidative stress
  • Squamous cell carcinoma
  • Wnt signaling

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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