Sulf-2, a Proangiogenic Heparan Sulfate Endosulfatase, Is Upregulated in Breast Cancer

Abstract

Sulf-2 is an endosulfatase with activity against glucosamine-6-sulfate modifications within subregions of intact heparin. The enzyme has the potential to modify the sulfation status of extracellular heparan sulfate proteoglycan (HSPG) glycosaminoglycan chains and thereby to regulate interactions with HSPG-binding proteins. In the present investigation, data mining from published studies was employed to establish Sulf-2 mRNA upregulation in human breast cancer. We further found that cultured breast carcinoma cells expressed Sulf-2 mRNA and released enzymatically active proteins into conditioned medium. In two mouse models of mammary carcinoma, Sulf-2 mRNA was upregulated in comparison to its expression in normal mammary gland. Although mRNA was present in normal tissues, Sulf-2 protein was undetectable; it was, however, detected in some premalignant lesions and in tumors. The protein was localized to the epithelial cells of the tumors. In support of the possible mechanistic relevance of Sulf-2 upregulation in tumors, purified recombinant Sulf-2 promoted angiogenesis in the chick chorioallantoic membrane assay.

Dynamic expression patterns of 6‐O endosulfatases during zebrafish development suggest a subfunctionalisation event for sulf2

“…In pancreatic tumours, human SULF2 increases tumour growth mediated by WNT signalling (Nawroth et al, 2007), which is consistent with a pro-angiogenic role of SULF2 in the chick chorioallantoic membrane assay (Morimoto-Tomita et al, 2005). It is possible, therefore, that tumour growth in cancer cells overexpressing SULF2 is potentiated by tumour angiogenesis.…”

Expression of Sulf1 and Sulf2 in cartilage, bone and endochondral fracture healing

“…This is compatible with little or no expression of such variants in most postnatal tissues except during acute injury compared with fetal (Gill et al 2010;Hitchins et al 2013) and particularly tumour tissues (Gill et al 2014). The requirement of only a very subtle change in the levels of shorter variants, not quantifiable by this method, or proximity to the hypertrophic chondrocytes expressing high levels of full length SULF2, which has been described to have some pro-angiogenic function (Morimoto-Tomita et al 2005), may be sufficient to promote angiogenesis in sub-chondral bone.…”

“…Differential SULF1/SULF2 expression in hypertrophic chondrocytes may thus indicate their differential roles in vascularisation as has been suggested by the antiangiogenic activities of SULF1 (Sahota and Dhoot 2009;Wang et al 2004) but a pro-angiogenic activity of SULF2 in some mammary tumours (Morimoto-Tomita et al 2005). …”

Functional Consequences of the Subdomain Organization of the Sulfs

“…The phenotypes in single and double null mice include abnormalities in general growth, muscle innervation, muscle regeneration, skeletal tissue, and lung development. The Sulfs have been extensively investigated in cancer with some studies consistent with tumor suppression activity (15,21,22) and others with a pro-oncogenic role (23)(24)(25).As is the case for the prototypic QSulf-1 (8), HSulf-1 and HSulf-2 consist of four domains from the N to C terminus: a signal peptide, a catalytic domain of 374 amino acids, a basic hydrophilic domain of 346/366 amino acids, and a C-terminal domain of 109/127 amino acids (7,8). In the 17-member sulfatase family (26), the Sulfs share the most extensive sequence homology with lysosomal glucosamine-6-sulfatase in the catalytic and C-terminal domains, although the centrally inserted hydrophilic domain is absent from this enzyme and other sulfatases.…”