Research Article: Retinoids induce antagonism between FOXO3A and FOXM1 transcription factors in human oral squamous cell carcinoma (OSCC) cells

Date Published: April 12, 2019

Publisher: Public Library of Science

Author(s): Kwame Osei-Sarfo, Lorraine J. Gudas, Andrei L. Gartel.


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.

Partial Text

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]. Thus, understanding the molecular signaling mechanisms that lead to OSCC is critical for the development of new therapies for OSCC.