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.

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 acids 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 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.

• Authors: Yu-Ting Chou, Jeng-Kai Jiang, Muh-Hwa Yang, Jeng-Wei Lu, Hua-Kuo Lin, Horng-Dar Wang, Chiou-Hwa Yuh
• Journal: PLoS biology (PLoS Biol) Vol. 16 Issue 1 Pg. e2003714 (01 2018) ISSN: 1545-7885 [Electronic] United States
• PMID: 29337987 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• RNA, Messenger
• beta Catenin
• Aldose-Ketose Isomerases
• ribosephosphate isomerase

Topics

• Adenomatous Polyposis Coli (metabolism)
• Adult
• Aged
• Aldose-Ketose Isomerases (metabolism, physiology)
• Animals
• Animals, Genetically Modified
• Carcinogenesis
• Cell Line, Tumor
• Cell Nucleus
• Cell Proliferation (physiology)
• Cell Transformation, Neoplastic
• Colorectal Neoplasms (genetics, metabolism)
• Female
• Humans
• Male
• Middle Aged
• Phosphorylation
• Promoter Regions, Genetic (genetics)
• Protein Domains
• RNA, Messenger (genetics)
• Ubiquitination
• Zebrafish
• beta Catenin (genetics, physiology)