Inhibition of SIRT7 Overcomes Radioresistance in Pancreatic Neuroendocrine Tumors by Reactivating MEN1 Expression

ABSTRACT Pancreatic neuroendocrine tumors (PanNETs) frequently exhibit loss or reduced expression of the tumor suppressor MEN1, a key regulator of tumor progression and DNA damage response (DDR). However, the upstream mechanisms driving MEN1 silencing remain unclear. Here, a pooled epigenetic CRISPR–Cas9 screen identified the NAD ⁺ ‐dependent deacetylase SIRT7 as a critical suppressor of MEN1 expression. Mechanistically, SIRT7 interacts with DNMT1 and promotes catalytic activity‐dependent recruitment of DNMT1 to the MEN1 promoter, leading to promoter hypermethylation and transcriptional repression. Clinically, SIRT7 is overexpressed in PanNET tissues and inversely correlates with MEN1 levels and patient prognosis. Genetic or pharmacologic inhibition of SIRT7 restored MEN1 expression, reduced MRN complex abundance, and impaired double‐strand break repair. Graded MEN1 re‐expression demonstrated a quantitative relationship between MRN levels, DNA repair efficiency, and radiosensitivity. Functionally, SIRT7 inhibition enhanced radiation‐induced DNA damage and apoptosis in a partially MEN1‐dependent manner and significantly suppressed tumor growth in patient‐derived organoids and multiple independent xenograft models. Collectively, these findings define a catalytic activity‐dependent SIRT7–DNMT1–MEN1 epigenetic axis that modulates DDR and radiosensitivity, supporting SIRT7 targeting as a strategy to improve radiotherapy efficacy in PanNETs.