Abstract
To gain a greater understanding of oral squamous cell carcinoma (OSCC) we investigated the actions of all-trans-retinoic acid (RA; a retinoid), bexarotene (a pan-RXR agonist), and forkhead box (FOX) transcription factors in human OSCC-derived cell lines. RA and bexarotene have been shown to limit several oncogenic pathways in many cell types. FOXO proteins typically are associated with tumor suppressive activities, whereas FOXM1 acts as an oncogene when overexpressed in several cancers. RA and/or bexarotene increased the transcript levels of FOXO1, FOXO3A, and TRAIL receptors; reduced the transcript levels of FOXM1, Aurora kinase B (AURKB), and vascular endothelial growth factor A (VEGFA); and decreased the proliferation of OSCC-derived cell lines. Also, RA and/or bexarotene influenced the recruitment of FOXO3A and FOXM1 to target genes. Additionally, FOXM1 depletion reduced cell proliferation, decreased transcript levels of downstream targets of FOXM1, and increased transcript levels of TRAIL receptors. Overexpression of FOXO3A decreased proliferation and increased binding of histone deacetylases (HDACs) 1 and 2 at the FOXM1, AURKB, and VEGFA promoters. This research suggests novel influences of the drugs RA and bexarotene on the expression of FOXM1 and FOXO3A in transcriptional regulatory pathways of human OSCC.
Highlights
Oral squamous cell carcinomas (OSCCs) are a heterogeneous group of cancers that develop in the epithelial tissues of the tongue, hard and soft palate, retromolar trigone, gums, buccal mucosa, and lip [1]
To determine if retinoic acid (RA), bexarotene (Bex), or the co-administration of RA plus bexarotene (RA+Bex) changed the transcript levels of various forkhead box (FOX) transcription factors, we quantified the changes in FOXO1, FOXO3A, and FOXM1 in the SCC-25 and SCC-4 human cell lines by Quantitative Real-Time PCR (QRT-PCR) (Fig 1)
We focused on the FOXO3 subfamily because FOXO3A was shown to regulate the transcription of FOXO1 in human OSCC, suggesting that FOXO1 is downstream of FOXO3 signaling [36]
Summary
Oral squamous cell carcinomas (OSCCs) are a heterogeneous group of cancers that develop in the epithelial tissues of the tongue, hard and soft palate, retromolar trigone, gums, buccal mucosa, and lip [1]. At the end of 2017, the estimated new cases and deaths resulting from OSCC world-wide were 1,688,780 and 600,920, respectively [2]. The 5-year survival rate of OSCC has not significantly changed over the past few decades, despite advances in surgery, chemotherapy, and radiation [3, 4]. Initiation and development of OSCC have been linked to high consumption of tobacco and alcohol, viral infection, and poor oral hygiene [5, 6].
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