The significance of post-translational removal of α-DG-N in early stage endometrial cancer development

// Sophea Heng 1, 2, 3 , Jemma Evans 1, 2, 4 , Lois A. Salamonsen 1, 2, 4 , Tom W. Jobling 4, 5 and Guiying Nie 1, 2, 3 1 Centre for Reproductive Health, Hudson Institute of Medical Research, Clayton, Victoria, Australia 2 Department of Molecular and Translational Sciences, Monash University, Clayton, Victoria, Australia 3 Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia 4 Department of Obstetrics and Gynaecology, Monash University, Clayton, Victoria, Australia 5 Epworth Research Institute, Epworth Health Care, Richmond, Victoria, Australia Correspondence to: Guiying Nie, email: guiying.nie@hudson.org.au Keywords: endometrial cancer, dystroglycan, tight junction, cell polarity, estrogen Received: October 25, 2016      Accepted: April 11, 2017      Published: April 20, 2017 ABSTRACT Endometrial cancer is one of the most common gynecological malignancies affecting post-menopausal women, yet the underlying mechanisms are not well understood. Dystroglycan (DG) is a large glycoprotein, consisting of α- and β-subunits that are non-covalently associated with each other. Modifications to α-DG have been linked to a variety of cancers, where the N-terminus of α-DG (α-DG-N) is post-translationally removed by a furin-like enzyme. However, the functional significance of α-DG-N removal is unknown. Our previous studies have established that the α-DG cleavage enzyme furin is significantly up-regulated in endometrial cancer. This study aimed to investigate the importance of α-DG-N removal in post-menopausal endometrial cancer. We demonstrated that α-DG-N removal predominantly occurred in early stage endometrial cancer tissues, and that the cleaved α-DG-N was significantly elevated in the uterine lavage of early grade endometrial cancer patients. Furthermore, α-DG-N removal significantly decreased the tight junction integrity and polarity of the endometrial epithelial cells, promoting the loss of polarity markers scribble and atypical protein kinase C (aPKC) and reducing the trans-epithelial electrical resistance. The removal of α-DG-N also sensitized the cells for estrogen-dependent proliferation. These results strongly suggest that α-DG-N removal plays an important role in early stage development of endometrial cancer, and that the elevated levels of α-DG-N in uterine fluid may provide a biomarker for early detection of endometrial cancer.