Investigation of control of histone chaperones by sphingosine kinase 2/S1P and its impact on the biogenesis of oral squamous cell carcinoma

• Grant number: 22/07171-4
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: June 01, 2023
• Status: Discontinued
• Field of knowledge: Health Sciences - Dentistry
• Principal Investigator: Andréia Machado Leopoldino
• Grantee: Graziella Ribeiro de Sousa
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 16/19103-2 - SET and sphingolipids in head and neck squamous cell carcinoma: signaling, targets and antiumoral therapy, AP.TEM
• Associated scholarship(s): 24/08728-8 - Reprogramming of FACT complex as a potential therapeutic target in cancer-associated fibroblasts and oral carcinoma using zebrafish model., BE.EP.PD

Abstract

Oral squamous cell carcinoma (OSCC) is a highly invasive and metastatic tumor, resistant to current multimodal therapies, mirroring therapeutic failure. Therefore, a better understanding of CEO biogenesis's molecular mechanisms is necessary. It is known that the biomolecules of the sphingolipid (SPs) metabolic pathway, such as sphingosine kinases 2 (SK2) and sphingosines-1-phosphate (S1P) are involved in epigenetic regulation processes, invasion, metastasis, and tumor resistance. In addition, histone chaperones from the FACT complex actively participate as key chromatin regulators during the steps of the invasion-metastasis cascade and might be SK2/S1P-regulated targets in driving DSC progression. Hence, to extend the studies of SK2 and investigate its epigenetic control in the induction of aggressive phenotypes in CEO; this project seeks to investigate the impact of SK2/S1P modulation on invasive and metastatic processes in experimental spheroid models (3D) and in vivo, using Zebrafish embryos. Subsequently, studies will be carried out to reveal the cooperation of SK2/S1P with histone chaperones (FACT complex) in the chromatin reprogramming of promoter regions of target genes by immunofluorescence, co-immunoprecipitation, and CHIP-Seq. After dissecting the complex interactions between SK2/S1P and the FACT complex, we will evaluate the impact of pharmacological inhibition of the FACT complex in blocking the spread of tumor cells in the aforementioned experimental models. This work is part of the thematic project approved by FAPESP (FAPESP Process: 2016/19103-2): "SET and sphingolipids in head and neck cancer: signaling, targets and antitumor therapy" and the proposed studies will allow describing a new "arm" of SK2/S1P signaling, indicating potential avenues for the development of new therapeutic interventions against recurrence and metastases in patients with CEO.