KRAS Promotes GLI2-Dependent Transcription during Pancreatic Carcinogenesis.
Cancer Res Commun
; 4(7): 1677-1689, 2024 Jul 01.
Article
en En
| MEDLINE
| ID: mdl-38896052
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.
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Base de datos:
MEDLINE
Asunto principal:
Neoplasias Pancreáticas
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Regulación Neoplásica de la Expresión Génica
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Proteínas Proto-Oncogénicas p21(ras)
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Carcinoma Ductal Pancreático
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Proteína Gli2 con Dedos de Zinc
Idioma:
En
Revista:
Cancer Res Commun
Año:
2024
Tipo del documento:
Article