Heparanase in cancer progression: Structure, substrate recognition and therapeutic potential

Abstract

Heparanase, a member of the carbohydrate-active enzyme (CAZy) GH79 family, is an endo-β-glucuronidase capable of degrading the carbohydrate moiety of heparan sulphate proteoglycans, thus modulating and facilitating remodeling of the extracellular matrix. Heparanase activity is strongly associated with major human pathological complications, including but not limited to tumour progress, angiogenesis and inflammation, which make heparanase a valuable therapeutic target. Long-due crystallographic structures of human and bacterial heparanases have been recently determined. Though the overall architecture of human heparanase is generally comparable to that of bacterial glucuronidases, remarkable differences exist in their substrate recognition mode. Better understanding of regulatory mechanisms of heparanase in substrate recognition would provide novel insight into the anti-heparanase inhibitor development as well as potential clinical applications.

Keywords: cancer; glycosaminoglycan (GAG); heparanase; structure; substrate recognition.

FIGURE 1

Cleavage of the glycosidic bond by HPSE. (A) The internal β(1,4)-linked glycosidic bond between GlcA and GlcNS is highlighted by an arrow in red; (B) The overall fold of hHPSE is illustrated in ribbon representation with α-helix in red, β-strand in yellow and loop in green.

FIGURE 2

HPSE substrate binding site and structural superimposition. (A) hHPSE (electrostatic surface) in complex with a bound tetrasaccharide (our unpublished work) in stick presentation (carbon in yellow, nitrogen in blue and oxygen in red) spanning through binding subsites +1, −1, −2, −3 (Davies et al., 1997); (B) BpHPSE is illustrated in surface representation with two conserved catalytic glutamate highlighted in red; the loop that forms part of the substrate-binding pocket in AcaGH79 is colored in magenta; the 6-kDa linker of hproHPSE is illustrated in ribbon representation with α-helix in red, β-strand in yellow and loop in green; the bound GlcA are colored with carbon in yellow and oxygen in red.

FIGURE 3

Roles of HPSE in cancer progression. (A) HPSE modulates cancer progression by mediating oncogenic signaling and proliferative signaling; (B) HPSE promotes cancer by resisting cell death, initiating angiogenesis, contributing to anti-immunity failure, circumventing growth inhibition and reprogramming energy metabolism.