The heparan sulfate degrading enzyme heparanase is up‐regulated by the EWS‐Fli1 fusion protein in Ewing sarcoma

Abstract

Ewing sarcoma is an aggressive form of bone and soft tissue cancer that predominantly affects adolescents. It is commonly caused by the partial translocation of the Ewing sarcoma protein (EWS) gene to the gene encoding the Ets family transcription factor Fli1, resulting in the formation of the EWS‐Fli1 fusion protein. Ewing sarcoma is often highly metastatic, resulting in a poor survival rate of approximately 20%. Expression of the endoglycosidase heparanase (HPSE), a heparan sulfate‐degrading enzyme that contributes to extracellular matrix remodelling, is up‐regulated in approximately 90% of all cancers, including Ewing sarcoma, and possesses pro‐metastatic and ‐angiogenic functions. It is therefore not surprising that it is also a marker of poor prognosis for cancer patients. While increased expression of HPSE in Ewing sarcoma has been reported to correlate with increased tumour size, disease severity and a poor patient outcome, the mechanism by which HPSE expression is increased in Ewing sarcoma has not been defined. We have identified a novel link between the EWS‐Fli1 fusion protein and the expression of HPSE. Using a combination of patient‐derived samples and cell lines, we have been able to show that an increase in expression of EWS‐Fli1 correlates with increased HPSE expression and activity. We also demonstrated that increased EWS‐Fli1 expression is responsible for increased HPSE expression and enzymatic activity by binding to the HPSE gene promoter and driving its expression. These findings highlight a possible role for HPSE in the progression and prognosis of Ewing sarcoma that may contribute to the aggressive nature of the disease.Support or Funding InformationAustralian National Health and Medical Research CouncilThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.