title: Proteasomal degradation of Atoh1 by aberrant Wnt signaling maintains the undifferentiated state of colon cancer.
abstract: Atoh1 plays a crucial role in intestinal cell differentiation. We have demonstrated that its human homolog Hath1 protein is targeted by the Wnt-GSK3 axis, resulting in the proteasomal degradation in human colon cancer. However, the contribution of Hath1 degradation to the undifferentiated state of colon cancer remains unknown. In this study, we demonstrated that both constitutive expression of mutant Hath1 and stabilization of Hath1 protein by a GSK3 inhibitor in colon cancer cells increased the expression of MUC2 known as a representative function of differentiated goblet cells. This means that Hath1 protein degradation may be required for maintaining the undifferentiated state of colon cancers, and that GSK3 inhibitors have potential for use in cancer therapy.
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
authors.forename: Mikayo
authors.initials: M
authors.lastname: Aragaki
authors.forename: Kiichiro
authors.initials: K
authors.lastname: Tsuchiya
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Okamoto
authors.forename: Sanae
authors.initials: S
authors.lastname: Yoshioka
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Nakamura
authors.forename: Naoya
authors.initials: N
authors.lastname: Sakamoto
authors.forename: Takanori
authors.initials: T
authors.lastname: Kanai
authors.forename: Mamoru
authors.initials: M
authors.lastname: Watanabe
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000473:pathology / Q000503:physiopathology*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D018021:Lithium Chloride / Q000494:pharmacology; D055262:Mucin-2; D009077:Mucins / Q000096:biosynthesis; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D014158:Transcription, Genetic; D051153:Wnt Proteins / Q000502:physiology*
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D018021:Lithium Chloride; D055262:Mucin-2; D009077:Mucins; D046988:Proteasome Endopeptidase Complex; D012333:RNA, Messenger; D051153:Wnt Proteins; C500942:ATOH1 protein, human; C524625:MUC2 protein, human