In the present study, using myeloma cell lines we find that: (i) within the nucleus, heparanase is present in the soluble fraction, and it is also bound to insoluble chromatin; (ii) the presence of nuclear heparanase enhances acetylation of histone H3 and promotes an open chromatin conformation; (iii) heparanase binds the promoter region of syndecan-1, MMP9 and CCND1, three genes whose expression is upregulated by heparinase; and (iv) heparanase increases phosphorylation of PTEN, leading to enhanced PTEN stability thereby diminishing its function as a tumor suppressor. This evidence concerns the gene HPSE and plasma cell myeloma.