Loss of Trim24 (Tif1alpha) gene function confers oncogenic activity to retinoic acid receptor alpha.
Hepatocellular carcinoma (HCC) is a major cause of death worldwide. Here, we provide evidence that the ligand-dependent nuclear receptor co-regulator Trim24 (also known as Tif1alpha) functions in mice as a liver-specific tumor suppressor. In Trim24-null mice, hepatocytes fail to execute proper cell cycle withdrawal during the neonatal-to-adult transition and continue to cycle in adult livers, becoming prone to a continuum of cellular alterations that progress toward metastatic HCC. Using pharmacological approaches, we show that inhibition of retinoic acid signaling markedly reduces hepatocyte proliferation in Trim24-/- mice. We further show that deletion of a single retinoic acid receptor alpha (Rara) allele in a Trim24-null background suppresses HCC development and restores wild-type expression of retinoic acid-responsive genes in the liver, thus demonstrating that in this genetic background Rara expresses an oncogenic activity correlating with a dysregulation of the retinoic acid signaling pathway. Our results not only provide genetic evidence that Trim24 and Rara co-regulate hepatocarcinogenesis in an antagonistic manner but also suggest that aberrant activation of Rara is deleterious to liver homeostasis.
Khetchoumian
Konstantin
K
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Department of Functional Genomics, Centre National de la Recherche Scientifique UMR7104, Université Louis Pasteur, Collége de France, Illkirch, France.
Teletin
Marius
M
Tisserand
Johan
J
Mark
Manuel
M
Herquel
Benjamin
B
Ignat
Mihaela
M
Zucman-Rossi
Jessica
J
Cammas
Florence
F
Lerouge
Thierry
T
Thibault
Christelle
C
Metzger
Daniel
D
Chambon
Pierre
P
Losson
Régine
R
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D049109:Cell Proliferation; D016147:Genes, Tumor Suppressor; D022781:Hepatocytes / Q000166:cytology; D008113:Liver Neoplasms / Q000378:metabolism*; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics*; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors / Q000235:genetics*
D009687:Nuclear Proteins; C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors; C093517:transcriptional intermediary factor 1