A piRNA chemosensitizes doxorubicin in tongue squamous cell carcinoma by targeting FDFT1 and inhibiting the EIF3H/HIF1α/CYPOR axis.

Doxorubicin (DOX) is a classical chemotherapeutic for various cancers that acts by intercalating within the DNA strand and inhibiting the function of topoisomerase, resulting in DNA break-induced apoptosis. Acquired chemoresistance has become a challenge for DOX therapy, but the possible solutions to overcome this problem are under investigation in many cancers. Recently, piwi-interacting RNAs (piRNAs) have been reported to modulate the chemosensitivity of different chemo drugs in different cancers. In this study, through several molecular assays, we showed that a piRNA, piR-39980 enhances the chemosensitivity of DOX in tongue cancer by targeting farnesyl-diphosphate farnesyltransferase 1 (FDFT1), a key enzyme of cholesterol biosynthesis, and attenuates its oncogenic effect by suppressing migration, ROS generation, cell proliferation, and tumor spheroid formation and shifting the cellular population from the S phase to the Sub-G1 phase of the cell cycle. Mechanistically, suppression of FDFT1 leads to inhibition of CYPOR and the EIF3H/HIF1α axis. The inhibition of CYPOR increases drug accumulation, and the EIF3H/HIF1α axis induces DNA break-mediated apoptosis, resulting in enhanced activity of DOX in tongue cancer cells. These findings suggest this piRNA can be used in combination with the chemotherapeutic drug to enhance its sensitivity in treating tongue cancer.