The acquisition of malignant potential in colon cancer is regulated by the stabilization of Atonal homolog 1 protein

Biochem Biophys Res Commun. 2013 Mar 1;432(1):175-81. doi: 10.1016/j.bbrc.2013.01.034. Epub 2013 Jan 16.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma, Mucinous / genetics
  • Adenocarcinoma, Mucinous / pathology*
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cell Cycle Checkpoints
  • Cell Movement
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / pathology*
  • Drug Resistance, Neoplasm
  • G1 Phase
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Mutation
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology
  • Protein Stability
  • Receptors, G-Protein-Coupled / genetics
  • Receptors, G-Protein-Coupled / metabolism
  • Resting Phase, Cell Cycle
  • Wnt Signaling Pathway*


  • ATOH1 protein, human
  • Basic Helix-Loop-Helix Transcription Factors
  • LGR5 protein, human
  • Receptors, G-Protein-Coupled