3021 - The Role of SIRT2 in Oral Stem Cell Resilience in Radiation Mucositis

05:00pm - 06:00pm PT

Hall F

Screen: 1

POSTER

Presenter(s)

Eva Allen, BS - University of Arkansas for Medical Sciences, Little Rock, AR

M. Patra, E. Allen, R. Sadhukhan, F. Kalantari, H. Allam, and F. Xia; Department of Radiation Oncology, University of Arkansas for Medical Sciences, Little Rock, AR

Purpose/Objective(s):

Radiation-induced oral mucositis (RIOM) is a debilitating side effect of radiotherapy for head and neck squamous cell carcinoma (HNSCC), often disrupting treatment. With no FDA-approved therapy, its pathogenesis remains unclear but involves oxidative stress and DNA damage from ionizing radiation (IR). SIRT2, an NAD+-dependent deacetylase, supports tumor suppression, longevity, and tissue protection. We hypothesize that SIRT2 regulates epithelial stem cell DNA repair, influencing RIOM.

Materials/Methods:

SIRT2 activity was modulated genetically using transgenic mice with SIRT2 overexpression (SIRT2-KI) or knockout (SIRT2-KO) and pharmacologically via nicotinamide riboside (NR) in vivo and NAD+ in vitro. Mice received localized oral irradiation, and RIOM severity was assessed by ulcer size, epithelial thickness, and structural integrity (H&E staining). DNA double-strand break (DSB) repair in epithelial stem cells was analyzed using ?-H2AX (DSB marker) and RAD51 (HR repair marker) co-immunofluorescence, with p63 identifying stem cells. Cytotoxicity assays evaluated IR response in vitro, while in vivo studies assessed tumor control in orthotopic HNSCC models.

Results:

Both genetic and pharmacological activation of SIRT2 were shown to protect mice from developing RIOM. Mechanistically, SIRT2 enhances the repair of DNA DSBs by promoting HR-mediated repair, which safeguards the oral mucosal stem cell population and reduces the severity of RIOM in irradiated mouse tongues. Importantly, pharmacological activation of SIRT2 using NAD+ in vitro and NR in vivo did not compromise the tumor response to IR, ensuring the therapeutic benefit without reducing cancer treatment efficacy.

Conclusion:

These findings establish SIRT2 activation as a promising strategy to mitigate RIOM while preserving tumor response to radiotherapy. Pharmacological activation of SIRT2 maintained mucosal integrity without compromising cancer treatment efficacy, highlighting its translational potential in radiation oncology.