101. KRAS Promotes GLI2-Dependent Transcription during Pancreatic Carcinogenesis.
- Author
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Sigafoos AN, Tolosa EJ, Carr RM, Fernandez-Barrena MG, Almada LL, Pease DR, Hogenson TL, Raja Arul GL, Mousavi F, Sen S, Vera RE, Marks DL, Flores LF, LaRue-Nolan KC, Wu C, Bamlet WR, Vrabel AM, Sicotte H, Schenk EL, Smyrk TC, Zhang L, Rabe KG, Oberg AL, Zaphiropoulos PG, Chevet E, Graham RP, Hagen CE, di Magliano MP, Elsawa SF, Pin CL, Mao J, McWilliams RR, and Fernandez-Zapico ME
- Subjects
- Animals, Humans, Mice, Carcinogenesis, Cell Line, Tumor, Histones metabolism, Histones genetics, Mice, Transgenic, Promoter Regions, Genetic genetics, Transcription, Genetic, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal pathology, Carcinoma, Pancreatic Ductal metabolism, Gene Expression Regulation, Neoplastic, Pancreatic Neoplasms genetics, Pancreatic Neoplasms pathology, Pancreatic Neoplasms metabolism, Proto-Oncogene Proteins p21(ras) genetics, Proto-Oncogene Proteins p21(ras) metabolism, Zinc Finger Protein Gli2 genetics, Zinc Finger Protein Gli2 metabolism
- Abstract
Aberrant activation of GLI transcription factors has been implicated in the pathogenesis of different tumor types including pancreatic ductal adenocarcinoma. However, the mechanistic link with established drivers of this disease remains in part elusive. In this study, using a new genetically engineered mouse model overexpressing constitutively active mouse form of GLI2 and a combination of genome-wide assays, we provide evidence of a novel mechanism underlying the interplay between KRAS, a major driver of pancreatic ductal adenocarcinoma development, and GLI2 to control oncogenic gene expression. These mice, also expressing KrasG12D, show significantly reduced median survival rate and accelerated tumorigenesis compared with the KrasG12D only expressing mice. Analysis of the mechanism using RNA sequencing demonstrate higher levels of GLI2 targets, particularly tumor growth-promoting genes, including Ccnd1, N-Myc, and Bcl2, in KrasG12D mutant cells. Furthermore, chromatin immunoprecipitation sequencing studies showed that in these cells KrasG12D increases the levels of trimethylation of lysine 4 of the histone 3 (H3K4me3) at the promoter of GLI2 targets without affecting significantly the levels of other major active chromatin marks. Importantly, Gli2 knockdown reduces H3K4me3 enrichment and gene expression induced by mutant Kras. In summary, we demonstrate that Gli2 plays a significant role in pancreatic carcinogenesis by acting as a downstream effector of KrasG12D to control gene expression., (©2024 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2024
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