title: Senescence-associated SIN3B promotes inflammation and pancreatic cancer progression.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is strikingly resistant to conventional therapeutic approaches. We previously demonstrated that the histone deacetylase-associated protein SIN3B is essential for oncogene-induced senescence in cultured cells. Here, using a mouse model of pancreatic cancer, we have demonstrated that SIN3B is required for activated KRAS-induced senescence in vivo. Surprisingly, impaired senescence as the result of genetic inactivation of Sin3B was associated with delayed PDAC progression and correlated with an impaired inflammatory response. In murine and human pancreatic cells and tissues, levels of SIN3B correlated with KRAS-induced production of IL-1α. Furthermore, evaluation of human pancreatic tissue and cancer cells revealed that Sin3B was decreased in control and PDAC samples, compared with samples from patients with pancreatic inflammation. These results indicate that senescence-associated inflammation positively correlates with PDAC progression and suggest that SIN3B has potential as a therapeutic target for inhibiting inflammation-driven tumorigenesis.
authors.forename: Maïté
authors.initials: M
authors.lastname: Rielland
authors.forename: David J
authors.initials: DJ
authors.lastname: Cantor
authors.forename: Richard
authors.initials: R
authors.lastname: Graveline
authors.forename: Cristina
authors.initials: C
authors.lastname: Hajdu
authors.forename: Lisa
authors.initials: L
authors.lastname: Mara
authors.forename: Beatriz de Diego
authors.initials: Bde D
authors.lastname: Diaz
authors.forename: George
authors.initials: G
authors.lastname: Miller
authors.forename: Gregory
authors.initials: G
authors.lastname: David
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D016922:Cellular Senescence / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D053582:Interleukin-1alpha / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C508584:IL1A protein, human; D053582:Interleukin-1alpha; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; C492042:SIN3B protein, human; C115812:Sin3b protein, mouse; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins