title: Enhancement of TGF-β signaling responses by the E3 ubiquitin ligase Arkadia provides tumor suppression in colorectal cancer.
abstract: TGF-β signaling provides tumor protection against colorectal cancer (CRC). Mechanisms that support its tumor-suppressive properties remain unclear. The ubiquitin ligase Arkadia/RNF111 enhances TGF-β signaling responses by targeting repressors of the pathway for degradation. The corepressors SnoN/Ski, critical substrates of Arkadia, complex with the activated TGF-β signaling effectors Smad2/3 (pSmad2/3) on the promoters of target genes and block their transcription. Arkadia degrades this complex including pSmad2/3 and unblocks the promoter. Here, we report that Arkadia is expressed highly in the mouse colonic epithelium. Heterozygous Akd(+/-) mice are normal but express less Arkadia. This leads to reduced expression of several TGF-β target genes, suggesting that normal levels of Arkadia are required for efficient signaling responses. Critically, Akd(+/-) mice exhibit increased susceptibility to azoxymethane/dextran sodium sulfate carcinogen-induced CRC, as they develop four-fold more tumors than wild-type mice. Akd(+/-) tumors also exhibit a more aggressive pathology, higher proliferation index, and reduced cytostasis. Therefore, Arkadia functions as a tumor suppressor whose peak expression is required to suppress CRC development and progression. The accumulation of nuclear SnoN and pSmad2, along with the downregulation of TGF-β target genes observed in Akd(+/-) colon and tumors, suggest that tumor-suppressing properties of Arkadia are mediated by its ability to derepress TGF-β signaling. Consistent with this likelihood, we identified mutations in primary colorectal tumors from human patients that reduce Arkadia function and are associated with the accumulation of nuclear SNON. Collectively, our findings reveal that Arkadia enhances TGF-β signaling responses and supports its tumor-suppressing properties in CRC.
authors: Department of Experimental Medicine, Imperial College, Hammersmith Hospital Campus, London, United Kingdom.
authors: Vikas
authors: V
authors: Sharma
authors: Anna G
authors: AG
authors: Antonacopoulou
authors: Shinya
authors: S
authors: Tanaka
authors: Alexios A
authors: AA
authors: Panoutsopoulos
authors: Vasiliki
authors: V
authors: Bravou
authors: Haralabos P
authors: HP
authors: Kalofonos
authors: Vasso
authors: V
authors: Episkopou
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D001397:Azoxymethane / Q000633:toxicity; D001483:Base Sequence; D003106:Colon / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000139:chemically induced / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D012720:Severity of Illness Index; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C060615:SKIL protein, human; C497782:SMAD2 protein, human; C486157:Skil protein, mouse; D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D016212:Transforming Growth Factor beta; D025521:Tumor Suppressor Proteins; C486067:RNF111 protein, human; C427283:Rnf111 protein, mouse; D044767:Ubiquitin-Protein Ligases; D001397:Azoxymethane