title: The acquisition of malignant potential in colon cancer is regulated by the stabilization of Atonal homolog 1 protein.
abstract: The transcription factor Atonal homolog 1 (Atoh1) plays crucial roles in the differentiation of intestinal epithelium cells. Although we have reported that the Atoh1 protein was degraded in colon cancer by aberrant Wnt signaling, a recent study has indicated that the Atoh1 protein is expressed in mucinous colon cancer (MC) and signet ring cell carcinoma (SRCC). However, the roles of the Atoh1 protein in MC are unknown. To mimic MC, a mutated Atoh1 protein was stably expressed in undifferentiated colon cancer cells. Microarray analysis revealed the acquisition of not only the differentiated cell form, but also malignant potential by Atoh1 protein stabilization. In particular, Atoh1 enhanced Wnt signaling, resulting in the induction of Lgr5 as a representative stem cell marker with the enrichment of cancer stem cells. Moreover, the fluorescent ubiquitination-based cell cycle indicator system with time-lapse live imaging demonstrated cell cycle arrest in the G0/G1 phase by Atoh1 protein stabilization. In conclusion, the Atoh1 protein regulates malignant potential rather than the differentiation phenotype of MC, suggesting the mechanism by which MC and SRCC are more malignant than non-mucinous adenocarcinoma.
authors: Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors: Yoshihito
authors: Y
authors: Kano
authors: Kiichiro
authors: K
authors: Tsuchiya
authors: Xiu
authors: X
authors: Zheng
authors: Nobukatsu
authors: N
authors: Horita
authors: Keita
authors: K
authors: Fukushima
authors: Shuji
authors: S
authors: Hibiya
authors: Yuhki
authors: Y
authors: Yamauchi
authors: Tatsunori
authors: T
authors: Nishimura
authors: Kunihiko
authors: K
authors: Hinohara
authors: Noriko
authors: N
authors: Gotoh
authors: Shinji
authors: S
authors: Suzuki
authors: Ryuichi
authors: R
authors: Okamoto
authors: Tetsuya
authors: T
authors: Nakamura
authors: Mamoru
authors: M
authors: Watanabe
mesh_terms: D002288:Adenocarcinoma, Mucinous / Q000235:genetics / Q000473:pathology*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D059447:Cell Cycle Checkpoints; D002465:Cell Movement; D003110:Colonic Neoplasms / Q000235:genetics / Q000473:pathology*; D019008:Drug Resistance, Neoplasm; D016193:G1 Phase; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D055550:Protein Stability; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D016192:Resting Phase, Cell Cycle; D060449:Wnt Signaling Pathway
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D043562:Receptors, G-Protein-Coupled; C500942:ATOH1 protein, human; C116884:LGR5 protein, human