SIRT6 cooperates with KDM5C to transcriptionally silence MICAL2 and inhibit tumorigenesis in pancreatic cancer

Pancreatic cancer is one of the most lethal malignancies, characterized by rapid progression, poor prognosis, and high mortality. Sirtuin 6 (SIRT6), a histone deacetylase, has been implicated in tumor suppression; however, its precise molecular mechanisms in pancreatic cancer progression and cancer stem cells (CSCs) regulation remain unclear. Pancreatic cancer cells were subjected to gain- and loss-of-function of SIRT6 and lysine demethylase 5 C (KDM5C) to investigate their roles in tumor progression. Protein interactions were analyzed using co-immunoprecipitation and GST pull-down assays. Genome-wide transcriptional and chromatin occupancy analyses were performed using RNA sequencing and chromatin immunoprecipitation sequencing to identify downstream targets of the SIRT6/KDM5C complex. Gene expression changes and signaling alterations were validated by RT–qPCR and western blotting. Functional assays, including EdU incorporation, tumor sphere formation, wound-healing, and transwell assays, were conducted to evaluate cell proliferation, stemness, and metastatic potential. Clinical relevance was assessed using public datasets and immunohistochemical analysis of patient samples. In vivo tumorigenesis was evaluated using xenograft mouse models. We report that SIRT6 interacts with KDM5C and that the expression of both proteins is downregulated in pancreatic cancer. Whole-genome analysis of the SIRT6/KDM5C complex revealed a series of target genes including MICAL2. Further studies demonstrated that the SIRT6/KDM5C complex binds to the promoter of MICAL2 to repress its transcription. Additionally, we found that SIRT6/KDM5C regulates target genes to suppress pancreatic cancer cell proliferation, metastasis, and stemness. In vivo experiments indicated that the absence of SIRT6/KDM5C promoted tumor xenograft growth in mice. Our findings demonstrate that the SIRT6/KDM5C complex acts as a critical regulator of pancreatic cancer progression by transcriptionally repressing MICAL2. This study highlights SIRT6 and KDM5C as potential biomarkers and therapeutic targets for pancreatic cancer.