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

• DOI: 10.1371/journal.pbio.2003714
• Publication Date: 2018-01-16T18:23:57Z
• Authors: Yu-Ting Chou; Jeng-Kai Jiang; Muh-Hwa Yang; Jeng-Wei Lu; Hua-Kuo Lin; Horng-Dar Wang; Chiou-Hwa Yuh
• Keywords: Adult; Male; QH301-705.5; Carcinogenesis; Animals, Genetically Modified; 03 medical and health sciences; Protein Domains; Cell Line, Tumor; Animals; Humans; RNA, Messenger; Biology (General); Phosphorylation; Promoter Regions, Genetic; Aldose-Ketose Isomerases; Aged; Cell Proliferation; Cell Nucleus; 0303 health sciences; Middle Aged; 3. Good health; Cell Transformation, Neoplastic; Adenomatous Polyposis Coli; Female; Colorectal Neoplasms; Research Article

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.