ZFIN ID: ZDB-PUB-180118-8
Identification of a noncanonical function for ribose-5-phosphate isomerase A promotes colorectal cancer formation by stabilizing and activating β-catenin via a novel C-terminal domain
Chou, Y.T., Jiang, J.K., Yang, M.H., Lu, J.W., Lin, H.K., Wang, H.D., Yuh, C.H.
Date: 2018
Source: PLoS Biology   16: e2003714 (Journal)
Registered Authors: Yuh, Chiou-Hwa (Cathy)
Keywords: none
MeSH Terms:
  • Adenomatous Polyposis Coli/metabolism
  • Adult
  • Aged
  • Aldose-Ketose Isomerases/metabolism*
  • Aldose-Ketose Isomerases/physiology*
  • Animals
  • Animals, Genetically Modified
  • Carcinogenesis
  • Cell Line, Tumor
  • Cell Nucleus
  • Cell Proliferation/physiology
  • Cell Transformation, Neoplastic
  • Colorectal Neoplasms/genetics
  • Colorectal Neoplasms/metabolism
  • Female
  • Humans
  • Male
  • Middle Aged
  • Phosphorylation
  • Promoter Regions, Genetic/genetics
  • Protein Domains
  • RNA, Messenger/genetics
  • Ubiquitination
  • Zebrafish
  • beta Catenin/genetics
  • beta Catenin/physiology*
PubMed: 29337987 Full text @ PLoS Biol.
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ABSTRACT
Altered metabolism is one of the hallmarks of cancers. Deregulation of ribose-5-phosphate isomerase A (RPIA) in the pentose phosphate pathway (PPP) is known to promote tumorigenesis in liver, lung, and breast tissues. Yet, the molecular mechanism of RPIA-mediated colorectal cancer (CRC) is unknown. Our study demonstrates a noncanonical function of RPIA in CRC. Data from the mRNAs of 80 patients' CRC tissues and paired nontumor tissues and protein levels, as well as a CRC tissue array, indicate RPIA is significantly elevated in CRC. RPIA modulates cell proliferation and oncogenicity via activation of β-catenin in colon cancer cell lines. Unlike its role in PPP in which RPIA functions within the cytosol, RPIA enters the nucleus to form a complex with the adenomatous polyposis coli (APC) and β-catenin. This association protects β-catenin by preventing its phosphorylation, ubiquitination, and subsequent degradation. The C-terminus of RPIA (amino acid 290 to 311), a region distinct from its enzymatic domain, is necessary for RPIA-mediated tumorigenesis. Consistent with results in vitro, RPIA increases the expression of β-catenin and its target genes, and induces tumorigenesis in gut-specific, promotor-carrying RPIA transgenic (Tg) zebrafish. Together, we demonstrate a novel function of RPIA in CRC formation in which RPIA enters the nucleus and stabilizes β-catenin activity and suggests that RPIA might be a biomarker for targeted therapy and prognosis.
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