Twist1 Suppresses Senescence Programs and Thereby Accelerates and Maintains Mutant Kras-Induced Lung Tumorigenesis

KRAS mutant lung cancers are generally refractory to chemotherapy as well targeted agents. To date, the identification of drugs to therapeutically inhibit K-RAS have been unsuccessful, suggesting that other approaches are required. We demonstrate in both a novel transgenic mutant Kras lung cancer mouse model and in human lung tumors that the inhibition of Twist1 restores a senescence program inducing the loss of a neoplastic phenotype. The Twist1 gene encodes for a transcription factor that is essential during embryogenesis. Twist1 has been suggested to play an important role during tumor progression. However, there is no in vivo evidence that Twist1 plays a role in autochthonous tumorigenesis. Through two novel transgenic mouse models, we show that Twist1 cooperates with KrasG12D to markedly accelerate lung tumorigenesis by abrogating cellular senescence programs and promoting the progression from benign adenomas to adenocarcinomas. Moreover, the suppression of Twist1 to physiological levels is sufficient to cause Kras mutant lung tumors to undergo senescence and lose their neoplastic features. Finally, we analyzed more than 500 human tumors to demonstrate that TWIST1 is frequently overexpressed in primary human lung tumors. The suppression of TWIST1 in human lung cancer cells also induced cellular senescence. Hence, TWIST1 is a critical regulator of cellular senescence programs, and the suppression of TWIST1 in human tumors may be an effective example of pro-senescence therapy

Crystal structure of the C-terminal WD40 repeat domain of the human Groucho/TLE1 transcriptional corepressor

AbstractGroucho (Gro)/TLE proteins are transcriptional corepressors that lack inherent DNA binding but interact with DNA-bound transcription factors and histones, and recruit histone deacetylases. Groucho-mediated repression is essential in embryonic development and involved in regulation of Wnt signaling in adult tissue. We have determined the 1.6 Å crystal structure of a C-terminal fragment of human Groucho/TLE1, comprising part of the Ser/Pro-rich region and a seven-bladed β propeller WD40 repeat domain, implicated in protein-protein interactions. The structure confirms the relationship to the yeast Tup1 corepressor, but reveals important structural differences specific to the metazoan system. Analysis of missense mutations in the C. elegans Groucho homolog UNC-37 identifies sites of interaction with repression effectors, and suggests an induced fit binding site for eh1 domains of Engrailed-type transcription factors