Fibrillarin Resists Cellular Senescence Via SIRT1‐Dependent Nicotinamide Metabolism and Its Inhibition Sensitizes Senolytic Therapy in Esophageal Squamous Cell Carcinoma

ABSTRACT

The importance of fibrillarin (FBL), an established nucleolar methyltransferase, was identified in neoplastic growth of esophageal squamous cell carcinoma (ESCC), one of the most lethal malignancies worldwide. However, the underlying mechanism remains unclear. Here, by enrolling independent ESCC cohorts, we verified the negative correlation between intratumoral FBL expression and patient prognosis. Notably, comprehensive transcriptomic and metabolomic analyses indicated that FBL deletion elicited cell cycle arrest and cellular senescence, as well as block of nicotinamide metabolism and increase of oxidative stress. Mechanistically, FBL could bind to and stabilize SIRT1 by obstructing the ubiquitin‐proteasome‐mediated protein degradation, therefore provoking nicotinamide metabolism, sustaining redox homeostasis, and counteracting senescence. Clinically, FBL‐SIRT1 axis was augmented in tumor tissues of ESCC patients, and high intratumoral SIRT1 expression predicted poor patient survival. Finally, we found that both genetic and pharmacological inhibition of FBL could sensitize senolytic therapy for ESCC. In conclusion, we first discovered FBL as an anti‐senescent protein in tumor progression. FBL resists cellular senescence by stabilizing SIRT1 and sustaining the nicotinamide metabolism, therefore providing an optional strategy for ESCC treatment by sensitizing senolytic therapy with FBL inhibitors.