The accumulation of sphingosine kinase 2 disrupts the DNA damage response and promotes resistance to genotoxic agents

There is a known correlation between cancer and changes in sphingolipids, specifically the production of sphingosine-1-phosphate (S1P) by sphingosine kinases 1 and 2 (SPHK1/SPHK2). However, a potential relationship between bioactive lipid molecules, SPHK, and the response to DNA damage is unknown. We aimed to evaluate the response of oral keratinocytes and head and neck cancer cell lines with SPHK2/S1P alterations to DNA damage. This assessment is intended to establish a link between these alterations and tumorigenesis as well as resistance to therapy. SPHK2 overexpression in oral squamous cells promoted evasion of apoptosis and cell cycle control, which increased the resistance to genotoxic agents (chemical and physical). Cells that have SPHK2 overexpression are more prone to DNA damage, which allows those damaged cells to survive and multiply. This is associated with a decrease in overall DNA methylation. These discoveries help to clarify the connection between SPHK2 and the response to DNA damage, as well as its capacity to aid in the resistance against genotoxic agents, including those used in cancer treatment.