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

Abstract

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.

FOXD1-mTOR Signaling Pathway on Oral Squamous Cell Carcinoma and Its Inhibition by Rosemary Extract (Invitro-Study)

“…Our FOXD1 results were consistent with Perri et al, (2017) and Lin et al, (2020) results showing upregulation of FOXD1 expression in oral squamous cell carcinoma cell lines. Furthermore, the study heavily suggested that FOXD1 would most probably play a key role during the OSCC tumorigenesis, delineating it as a novel diagnostic and prognostic biomarker for OSCC that is closely related to tumor invasion and metastasis.…”

SUMOylation of RALY promotes vasculogenic mimicry in glioma cells via the FOXD1/DKK1 pathway

“…FOXD1, a transcription factor, has been found to regulate the expression of genes downstream by directly binding to their promoters. In oral cancer cells, FOXD1 promotes the malignant progression of cells by upregulating G3BP2 expression via directly binding to its promoter (Lin et al 2020 ). As previously reported, DKK1 is upregulated in glioma cells and tissues, which is similar to the results of this study.…”

Identification of Antitumor miR-30e-5p Controlled Genes; Diagnostic and Prognostic Biomarkers for Head and Neck Squamous Cell Carcinoma

“…FOXD1 expression is upregulated in several types of cancers [ 46 ]. Moreover, the knockdown of FOXD1 impairs the colony-forming abilities of oral cancer cells after radiation treatment [ 47 ]. Another study showed that upregulated FOXD1 contributed to melanoma cells’ resistance to vemurafenib via the recruited expression of connective tissue growth factor [ 48 ].…”