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FOXD1 Repression Potentiates Radiation Effectiveness by Downregulating G3BP2 Expression and Promoting the Activation of TXNIP-Related Pathways in Oral Cancer

by 1,2,†, 3,4,5,6, 7, 1,8, 1,2,†, 9,10 and 3,11,*
1
Department of Otolaryngology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
2
Department of Otolaryngology, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan
3
Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
4
Department of Neurology, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235, Taiwan
5
Department of Neurology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
6
Department of Neurology, Vertigo and Balance Impairment Center, Shuang Ho Hospital, Taipei Medical University, New Taipei City 235, Taiwan
7
School of Oral Hygiene, College of Oral Medicine, Taipei Medical University, Taipei 11031, Taiwan
8
Department of Otolaryngology, Shuang-Ho Hospital, Taipei Medical University, New Taipei City 235, Taiwan
9
Department of Radiation Oncology, Taipei Medical University Hospital, Taipei Medical University, Taipei 11031, Taiwan
10
Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei 11031, Taiwan
11
Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan
*
Author to whom correspondence should be addressed.
The authors equally contributed to this study.
Cancers 2020, 12(9), 2690; https://doi.org/10.3390/cancers12092690
Received: 7 August 2020 / Revised: 15 September 2020 / Accepted: 16 September 2020 / Published: 21 September 2020
Radioresistance remains a critical issue in treating oral cancer patients. This study was thus aimed to identify a potential drug target for enhancing the therapeutic effectiveness of irradiation and uncover a possible mechanism for radioresistance in oral cancer. Here we show that FOXD1, a gene encoding forkhead box d1 (Foxd1), is significantly upregulated in primary tumors compared to normal tissues and serves as a poor prognostic marker in oral cancer patients receiving radiotherapy. FOXD1 repression by a gene knockdown experiment dramatically enhanced the cytotoxic efficacy of irradiation probably via activating the p53-related DNA repairing pathways and reinforcing the T cell-mediated immune responses in oral cancer cells. Our findings demonstrate that FOXD1 may play a pivotal role in conferring radioresistance, which might provide a new strategy to combat the irradiation-insensitive oral cancer cells via therapeutically targeting FOXD1 activity.
Radiotherapy is commonly used to treat oral cancer patients in the current clinics; however, a subpopulation of patients shows poor radiosensitivity. Therefore, the aim of this study is to identify a biomarker or druggable target to enhance the effectiveness of radiotherapy on oral cancer patients. By performing an in silico analysis against public databases, we found that the upregulation of FOXD1, a gene encoding forkhead box d1 (Foxd1), is extensively detected in primary tumors compared to normal tissues and associated with a poor outcome in oral cancer patients receiving irradiation treatment. Moreover, our data showed that the level of FOXD1 transcript is causally relevant to the effective dosage of irradiation in a panel of oral cancer cell lines. The FOXD1 knockdown (FOXD1-KD) dramatically suppressed the colony-forming ability of oral cancer cells after irradiation treatment. Differentially expressed genes analysis showed that G3BP2, a negative regulator of p53, is predominantly repressed after FOXD1-KD and transcriptionally regulated by Foxd1, as judged by a luciferase-based promoter assay in oral cancer cells. Gene set enrichment analysis significantly predicted the inhibition of E2F-related signaling pathway but the activation of the interferons (IFNs) and p53-associated cellular functions, which were further validated by luciferase reporter assays in the FOXD1-KD oral cancer cells. Robustly, our data showed that FOXD1-KD fosters the expression of TXNIP, a downstream effector of IFN signaling and activator of p53, in oral cancer cells. These findings suggest that FOXD1 targeting might potentiate the anti-cancer effectiveness of radiotherapy and promote immune surveillance on oral cancer. View Full-Text
Keywords: radiotherapy; FOXD1; G3BP2; TXNIP; oral cancer radiotherapy; FOXD1; G3BP2; TXNIP; oral cancer
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MDPI and ACS Style

Lin, C.-H.; Lee, H.-H.; Chang, W.-M.; Lee, F.-P.; Chen, L.-C.; Lu, L.-S.; Lin, Y.-F. FOXD1 Repression Potentiates Radiation Effectiveness by Downregulating G3BP2 Expression and Promoting the Activation of TXNIP-Related Pathways in Oral Cancer. Cancers 2020, 12, 2690. https://doi.org/10.3390/cancers12092690

AMA Style

Lin C-H, Lee H-H, Chang W-M, Lee F-P, Chen L-C, Lu L-S, Lin Y-F. FOXD1 Repression Potentiates Radiation Effectiveness by Downregulating G3BP2 Expression and Promoting the Activation of TXNIP-Related Pathways in Oral Cancer. Cancers. 2020; 12(9):2690. https://doi.org/10.3390/cancers12092690

Chicago/Turabian Style

Lin, Che-Hsuan, Hsun-Hua Lee, Wei-Min Chang, Fei-Peng Lee, Lung-Che Chen, Long-Sheng Lu, and Yuan-Feng Lin. 2020. "FOXD1 Repression Potentiates Radiation Effectiveness by Downregulating G3BP2 Expression and Promoting the Activation of TXNIP-Related Pathways in Oral Cancer" Cancers 12, no. 9: 2690. https://doi.org/10.3390/cancers12092690

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