Emergence of nuclear heparanase induces differentiation of human mammary cancer cells

Association of heparanase gene (HPSE) single nucleotide polymorphisms with hematological malignancies

“…14 Whether gene transcription and maintained cellular differentiation is due to direct interaction of heparanase with the DNA, or is a consequence of heparanase-mediated degradation of nuclear HS, is yet to be demonstrated. 8,9 MM is a B-lymphoid malignancy characterized by tumor cell infiltration of the bone marrow, osteolytic lesions and angiogenesis in the vicinity of the tumor cells. A subpopulation of myeloma cells within the human bone marrow expresses high levels of heparanase.…”

“…4,5 In addition to localization in the cytoplasm, most likely in lysosomes, heparanase was also noted to assume nuclear localization, demonstrated by cell fractionation and immunostaining of cultured cells and tumor biopsies. [6][7][8][9] Nuclear localization was correlated with cellular differentiation and favorable prognosis of cancer patients, 7,9 suggesting that heparanase is intimately involved in gene regulation. 8,9 The heparanase gene (HPSE) is located on chromosome 4q21.3 10 and expressed in a variety of normal cells, among which are cytotrophoblasts, endothelial cells, keratinocytes, mast cells and hematopoietic cells (that is, platelets, neutrophils, macrophages, T and B lymphocytes), mediating their extravasation during inflammatory and immune responses.…”

The endoglycosidase heparanase enters the nucleus of T lymphocytes and modulates H3 methylation at actively transcribed genes via the interplay with key chromatin modifying enzymes

“…[21][22][23][24] Similarly, transfection of tumor cells with mutant heparanases or heparanase fragments that lack enzymatic activity can result in enhanced tumor development and metastasis. 25,26 A number of studies have also reported the presence of heparanase in the nucleus of cells, [27][28][29][30] with nuclear heparanase being associated with a favorable prognosis and cytoplasmic heparanase with poor survival in patients with lung, neck and gastric cancers. 31 There is some evidence that nuclear heparanase expression is linked to cell differentiation 28,30,[32][33][34] but, despite such reports, the functional relevance of nuclear heparanase remains to be established.…”

Gem-diamine 1-N-iminosugars as versatile glycomimetics: synthesis, biological activity and therapeutic potential

“…A flexible synthetic route to four gem-diamine 1-N-iminosugars of D-and L-uronic acid type (D-glucuronic, D-mannuronic, L-iduronic and L-guluronic acid) from L-galactono-1,4-lactone was also developed in an enantiodivergent manner through a sequence involving as the key steps (1) the formation of gem-diamine 1-N-iminopyranose ring by the Mitsunobu reaction of an aminal (44)(45)46) and (2) the flexible introduction of a carboxylic acid group by the Wittig reaction on a ketone, followed by hydroboration and oxidation, as well as the Sharpless oxidation (45 and 46-47, 48 and 55, 56) (Schemes 4 and 5). 22,23 The diastereoselective construction of amino and carboxylic acid substituents at positions C-2 and C-5, respectively, on the versatile aminal 44 led to the formation of four enantiomerically pure stereoisomers (51, 54, 61 and 66).…”

“…46 On esophageal cell differentiation, heparanase is translocated from the cytoplasm to the nucleus. On such translocation, heparanase degrades the glycan chain of HS in the nucleus, and changes in the expression of keratinocyte differentiation markers such as p27 and involucrin are observed.…”