AACR 2014 --Jae-Hyun Park

Abstract Number: 3226
Presentation Title: GALNT6 stabilizes GRP78 protein by O-type glycosylation
Presentation Time: Tuesday, Apr 08, 2014, 8:00 AM -12:00 PM
Location: Hall A-E, Poster Section 11
Poster Board Number: 6
Author Block: Jae-Hyun Park1, Suyoun Chung1, Jiaying Lin1, Koji Ueda2, Toyomasa Katagiri3, Yusuke Nakamura11Department of Medicine, The University of Chicago, Chicago, IL; 2Laboratory for Biomarker Development, RIKEN, Yokohama, Japan; 3Division of Genome Medicine, The University of Tokushima, Tokushima, Japan
Abstract Body: Aberrant O-type glycosylation is predominantly detected in breast cancer and plays diverse roles in cancer cell proliferation, metastasis, and drug resistance. GALNT (polypeptide N-acetylgalactosaminyl transferase) family initiates the O-type glycosylation and its high activity accounts for aberrant O-type glycosylation in breast cancer. We previously suggested that GALNT6 is a promising molecular target in breast cancer and involved in O-type glycosylation of Mucin 1 and fibronectin. To further investigate the molecular function of GALNT6, we performed pull down assay using VVA (Vicia Villosa agglutinin) lectin and identified several O-glycosylated proteins specifically in GALNT6-positive stable cells. After in vitro and in vivo O-glycosylation assays, we confirmed GRP78 (glucose related protein 78) as a physiological substrate of GALNT6 and identified 5 O-glycosylation sites in GRP78 by mass spectrometry. GRP78 is a molecular chaperone that facilitates proper protein folding under cellular stress. Interestingly, accumulating evidences have indicated that GRP78 plays anti-apoptotic roles in cancer cells against chemotherapy. Exogenous induction of GALNT6 increased the amount of GRP78 protein without any changes in its transcriptional level. Concordantly, knockdown of GALNT6 significantly reduced the GRP78 protein. Collectively, our findings imply that GALNT6 stabilizes GRP78 via O-glycosylation and GALNT6 inhibitor will be able to sensitize breast cancer cells to chemotherapy.