β-1,4-Galactosyltransferase III suppresses β1 integrin-mediated invasive phenotypes and negatively correlates with metastasis in colorectal cancer

Abstract

Metastasis often occurs in colorectal cancer (CRC) patients and is the main difficulty in cancer treatment. The upregulation of poly-N-acetyllactosamine-related glycosylation is found in CRC patients and is associated with progression and metastasis in cancer. β-1,4-Galactosyltransferase III (B4GALT3) is an enzyme responsible for poly-N-acetyllactosamine synthesis, and therefore, we investigated its expression in CRC patients. We found that B4GALT3 negatively correlated with poorly differentiated histology (P < 0.001), advanced stages (P = 0.0052), regional lymph node metastasis (P = 0.0018) and distant metastasis (P = 0.0463) in CRC patients. B4GALT3 overexpression in CRC cells suppressed cell migration, invasion and adhesion, whereas B4GALT3 knockdown enhanced malignant cell phenotypes. The β1 integrin-blocking antibody reversed the B4GALT3-mediated increase in cell invasion. B4GALT3 expression altered glycosylation on the N-glycan of β1 integrin probably through changes in poly-N-acetyllactosamine expression. Furthermore, more activated β1 integrin along with the activation of its downstream signaling transduction were found in B4GALT3 knockdown cells, whereas overexpression of B4GALT3 suppressed the expression of active β1 integrin and inhibited its downstream signaling. Our results suggest that B4GALT3 is negatively associated with CRC metastasis and suppresses cell invasiveness through inhibiting activation of β1 integrin.

Association of N-Linked Glycoprotein Acetyls and Colorectal Cancer Incidence and Mortality

“…[17] Increased expression of some glycosyl moieties promotes invasion and metastasis, leading to shorter patient survival rates, whereas expression of other glycosyl epitopes suppresses tumor progression, resulting in higher survival rates. [26] Inflammation and immune function are united in the pathogenesis of cancers[27, 28] and underlie the mechanistic importance of protein post-translational glycosylation in the pathogenesis of CRC. [29]…”

β4GALT1 controls β1 integrin function to govern thrombopoiesis and hematopoietic stem cell homeostasis

“…Increased β4GalT1 expression and activity is significantly correlated with differentiation and mobilization of granulocytes and with the metastatic potential of specific cancer cells 37,[60][61][62][63][64] . Modifications of LacNAc by sialic acid and Gal decorations on α4β1 or α5β1 negatively affect cell-cell and cell-matrix interactions, thereby increasing cancer cell mobility in colon adenocarcinoma, ovarian cancer, and hepatocellular carcinoma 37,[64][65][66][67][68][69] . Control MKs express two β1 integrin glycoforms at 130 and 110 kDa, while platelets express the 130 kDa β1 glycoform primarily.…”

Identification of Mutations in Myocilin and Beta-1,4-galactosyltransferase 3 Genes in a Chinese Family with Primary Open-angle Glaucoma

“…[24] Recently, it has been reported that B4GALT3 protein plays an important role in invasion, proliferation, and metastasis in extravillous trophoblast, colorectal cancer, and neuroblastoma. [252627] The mutation of B4GALT3 gene was first identified in a POAG pedigree. POAG is a complex neurodegenerative disease which results in the stress in retinal ganglion cells and optic nerve axons.…”