RINT1 Regulates SUMOylation and the DNA Damage Response to Preserve Cellular Homeostasis in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) still presents with a dismal prognosis despite intense research. Better understanding of cellular homeostasis could identify druggable targets to improve therapy. Here we propose RAD50-interacting protein 1 (RINT1) as an essential mediator of cellular homeostasis in PDAC. In a cohort of resected PDAC, low RINTI protein expression correlated significantly with better survival. Accordingly, RINTI depletion caused severe growth defects in vitro associated with accumulation of DNA double-strand breaks (DSB), G(2) cell cycle arrest, disruption of Golgi-endoplasmic reticulum homeostasis, and cell death. Time-resolved transcriptomics corroborated by quantitative proteome and interactome analyses pointed toward defective SUMOylation after RINT1 loss, impairing nucleocytoplasmic transport and DSB response. Subcutaneous xenografts confirmed tumor response by RINTI depletion, also resulting in a survival benefit when transferred to an orthotopic model. Primary human PDAC organoids licensed RINTI relevance for cell viability. Taken together, our data indicate that RINTI loss affects PDAC cell fate by disturbing SUMOylation pathways. Therefore, a RINTI interference strategy may represent a new putative therapeutic approach. Significance: These findings provide new insights into the aggressive behavior of PDAC, showing that RINT1 directly correlates with survival in patients with PDAC by disturbing the SUMOylation process, a crucial modification in carcinogenesis.

Automated summary

Research has identified RINT1 as a crucial mediator of cellular homeostasis in PDAC, with its depletion potentially affecting the fate of PDAC cells. The study found that RINTI directly correlates with survival in patients with PDAC by disturbing the SUMOylation process, indicating a potential new therapeutic approach for this aggressive cancer.