2. Academic Validation
  3. PTC124 Rescues Nonsense Mutation of Two Tumor Suppressor Genes NOTCH1 and FAT1 to Repress HNSCC Cell Proliferation

PTC124 Rescues Nonsense Mutation of Two Tumor Suppressor Genes NOTCH1 and FAT1 to Repress HNSCC Cell Proliferation

  • Biomedicines. 2022 Nov 16;10(11):2948. doi: 10.3390/biomedicines10112948.
Ming-Han Wu 1,  Rui-Yu Lu 2,  Si-Jie Yu 2,  Yi-Zhen Tsai 2,  Ying-Chen Lin 2,  Zhi-Yu Bai 2,  Ruo-Yu Liao 2,  Yi-Chiang Hsu 1,  Chia-Chi Chen 3 4,  Bi-He Cai 1
Affiliations

Affiliations

  • 1 School of Medicine, I-Shou University, No.8, Yida Rd., Jiaosu Village Yanchao District, Kaohsiung City 82445, Taiwan.
  • 2 Department of Medical Laboratory Science, I-Shou University, No.8, Yida Rd., Jiaosu Village Yanchao District, Kaohsiung City 82445, Taiwan.
  • 3 Department of Pathology, E-Da Hospital, No.1, Yida Rd., Jiaosu Village Yanchao District, Kaohsiung City 82445, Taiwan.
  • 4 College of Medicine, I-Shou University, No.8, Yida Rd., Jiaosu Village Yanchao District, Kaohsiung City 82445, Taiwan.
PMID: 36428516 DOI: 10.3390/biomedicines10112948
Abstract

(1) Background: PTC124 (Ataluren) is an investigational drug for the treatment of nonsense mutation-mediated genetic diseases. With the exception of the TP53 tumor suppressor gene, there has been little research on cancers with nonsense mutation. By conducting a database search, we found that another two tumor suppressor genes, NOTCH1 and FAT1, have a high nonsense mutation rate in head and neck squamous cell carcinoma (HNSCC). PTC124 may re-express the functional NOTCH1 or FAT1 in nonsense mutation NOTCH1 or FAT1 in HSNCC (2) Methods: DOK (with NOTCH1 Y550X) or HO-1-u-1 (with FAT1 E378X) HNSCC cells were treated with PTC124, and the NOTCH1 or FAT1 expression, cell viability, and NOTCH1- or FAT1-related downstream gene profiles were assayed. (3) Results: PTC124 was able to induce NOTCH1 or FAT1 expression in DOK and HO-1-u-1 cells. PTC124 was able to upregulate Notch downstream genes HES5, AJUBA, and ADAM10 in DOK cells. PTC124 enhanced DDIT4, which is under the control of the FAT1-YAP1 pathway, in HO-1-u-1 cells. FLI-06 (a Notch signaling inhibitor) reversed PTC124-mediated cell growth inhibition in DOK cells. PTC124 could reverse TT-10 (a YAP signaling activator)-mediated HO-1-u-1 cell proliferation. (4) Conclusions: PTC124 can rescue nonsense mutation of NOTCH1 and FAT1 to repress HNSCC cell proliferation.

Keywords

FAT1; HNSCC; NOTCH1; PTC124; nonsense mutation.

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