6-O-endosulfatases in tumor metastasis: heparan sulfate proteoglycans modification and potential therapeutic targets

Abstract

Metastasis is the leading cause of cancer-associated mortality. Although advances in the targeted treatment and immunotherapy have improved the management of some cancers, the prognosis of metastatic cancers remains unsatisfied. Therefore, the specific mechanisms in tumor metastasis need further investigation. 6-O-endosulfatases (SULFs), comprising sulfatase1 (SULF1) and sulfatase 2 (SULF2), play pivotal roles in the post-synthetic modifications of heparan sulfate proteoglycans (HSPGs). Consequently, these extracellular enzymes can regulate a variety of downstream pathways by modulating HSPGs function. During the past decades, researchers have detected the expression of SULF1 and SULF2 in most cancers and revealed their roles in tumor progression and metastasis. Herein we reviewed the metastasis steps which SULFs participated in, elucidated the specific roles and mechanisms of SULFs in metastasis process, and discussed the effects of SULFs in different types of cancers. Moreover, we summarized the role of targeting SULFs in combination therapy to treat metastatic cancers, which provided some novel strategies for cancer therapy.

Keywords: HSPG; SULF1; SULF2; metastasis; therapeutic target.

Figure 1

The structure and function of HSPGs and SULFs. A. HSPGs are divided into extracellular, membranal and intracellular subtypes according to their cellular location. HSPGs are composed of the core proteins and HS chains. After biogenesis HSPGs undergo a series of modifications, among them SULFs catalyze hydrolysis of 6-O sulfates. B. The biogenesis of SULFs. SULFs are synthesized as preproproteins. After removal of the signal peptide, SULFs are cleaved by the furin-type proteinase and the fragments are joined by disulfide bonds. GlcA: glucuronic acid, GlcNAc: N-acetyl glucosamine, 2-OST: 2-sulfotransferase, 3-OST: 3-sulfotransferase, 6-OST: 6-sulfotransferase, NDST: N-deacetylase/N-sulfotransferase, GLCE: glucuronic acid epimerase, HPSE: heparinase.

Figure 2

Specific mechanisms of SULFs in tumor metastasis. SULFs mainly regulate tumor metastasis through influencing the HS-related signaling pathways. For each, the modifications of HS-chains by SULFs can affect the release of bio-active ligands or the formation of co-receptor complex. Various pathways are involved in and regulate the metastasis associated processes including proliferation, migration, invasion, EMT, angiogenesis and TME remodeling.

Figure 3

The expression of SULFs in different types of cancers. A, B. SULF1 and SULF2 have similar structure and desulfation function, but their expression varies in different cancers. The results were analyzed in TCGA database. GBMLGG: glioblastoma and low-grade glioma, GBM: glioblastoma multiforme, LGG: low-grade glioma, CESC: cervical squamous cell carcinoma, LUAD: lung adenocarcinoma, COAD: colon adenocarcinoma, COADREAD: colon adenocarcinoma and rectum adenocarcinoma, BRCA: breast invasive carcinoma, ESCA: Esophageal carcinoma, STES: stomach and esophageal carcinoma, KICH: kidney chromophobe, KIRP: kidney renal papillary cell carcinoma, KIRC: kidney renal clear cell carcinoma, KIPAN: pan-kidney cohort, STAD: stomach adenocarcinoma, PRAD: prostate adenocarcinoma, UCEC: uterine corpus endometrial carcinoma, HNSC: head and neck squamous cell carcinoma, LUSC: lung squamous cell carcinoma, LIHC: liver hepatocellular carcinoma, THCA: thyroid carcinoma, PAAD: pancreatic adenocarcinoma, BLCA: bladder urothelial carcinoma, CHOL: cholangiocarcinoma.