TGIF 1 functions as a tumor suppressor in pancreatic ductal adenocarcinoma

• DOI: 10.15252/embj.2018101067
• Publication Date: 2019-05-31T13:29:05Z
• Authors: Parash Parajuli; Purba Singh; Zhe Wang; Lianna Li; Sailaja Eragamreddi; Seval Ozkan; Olivier Ferrigno; Celine Prunier; Mohammed S Razzaque; Keli Xu; Azeddine Atfi
• Keywords: Homeodomain Proteins; 0301 basic medicine; Twist-Related Protein 1; Nuclear Proteins; Gene Expression Regulation, Neoplastic; Pancreatic Neoplasms; Proto-Oncogene Proteins p21(ras); Repressor Proteins; Disease Models, Animal; Mice; 03 medical and health sciences; Transforming Growth Factor beta; Cell Line, Tumor; [SDV.BBM] Life Sciences [q-bio]/Biochemistry, Molecular Biology; Disease Progression; Animals; Humans; [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology; Neoplasm Metastasis; Carcinoma, Pancreatic Ductal; Signal Transduction

A prominent function of TGIF1 is suppression of transforming growth factor beta (TGF-β) signaling, whose inactivation is deemed instrumental to the progression of pancreatic ductal adenocarcinoma (PDAC), as exemplified by the frequent loss of the tumor suppressor gene SMAD4 in this malignancy. Surprisingly, we found that genetic inactivation of Tgif1 in the context of oncogenic Kras, KrasG12D , culminated in the development of highly aggressive and metastatic PDAC despite de-repressing TGF-β signaling. Mechanistic experiments show that TGIF1 associates with Twist1 and inhibits Twist1 expression and activity, and this function is suppressed in the vast majority of human PDACs by KrasG12D /MAPK-mediated TGIF1 phosphorylation. Ablating Twist1 in KrasG12D ;Tgif1KO mice completely blunted PDAC formation, providing the proof-of-principle that TGIF1 restrains KrasG12D -driven PDAC through its ability to antagonize Twist1. Collectively, these findings pinpoint TGIF1 as a potential tumor suppressor in PDAC and further suggest that sustained activation of TGF-β signaling might act to accelerate PDAC progression rather than to suppress its initiation.