The glycosyltransferase GnT-III activates Notch signaling and drives stem cell expansion to promote the growth and invasion of ovarian cancer

Authors

Heba Allam, Menoufia University
Blake P. Johnson, Ouachita Baptist University
Mao Zhang, University of Arkansas for Medical Sciences
Zhongpeng Lu, University of Arkansas for Medical Sciences
Martin J. Cannon, University of Arkansas for Medical Sciences
Karen L. Abbott, University of Arkansas for Medical Sciences

Department

Biology

Document Type

Article

Publication Date

9-29-2017

Abstract

Glycosylation changes associated with cellular transformation can facilitate the growth and progression of tumors. Previously we discovered that the gene Mgat3 encoding the glycosyltransferase GnT-III is elevated in epithelial ovarian carcinomas (EOCs) and leads to the production of abnormal truncated N-linked glycan structures instead of the typical bisected forms. In this study, we are interested in discovering how these abnormal glycans impact the growth and progression of ovarian cancer. We have discovered using stable shRNA gene suppression that GnT-III expression controls the expansion of side-population cells, also known as cancer stem cells. More specifically, we found that GnT-III expression regulates the levels and activation of the heavily glycosylated Notch receptor involved in normal and malignant development. Suppression of GnT-III in EOC cell lines and primary tumor-derived cells resulted in an inhibition of Notch signaling that was more potent than phar-macologic blockage of Notch activation via γ-secretase inhibition. The inhibition resulted from the redirection of the Notch receptor to the lysosome, a novel mechanism. These findings demonstrate a new role for bisecting glycosylation in the control of Notch transport and demonstrate the therapeutic potential of inhibiting GnT-III as a treatment for controlling EOC growth and recurrence.

Publication Title

Journal of Biological Chemistry

Publisher Statement

Copyright © 2017 the Authors

DOI

10.1074/jbc.M117.783936

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.

Recommended Citation

Allam, Heba, Johnson, Blake P., Zhang, Mo, Lu, Zhongpeng, Cannon, Martin J., Abbot, Karen L. "The Glycosyltransferase GnT-III activates Notch Signaling and Drives Stem Cell Expansion to Promote the Growth and Invasion of Ovarian Cancer," Journal of Biological Chemistry (2017) 292(39): 16351-16359, https://doi.org/10.1074/jbc.M117.783936.