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At present, the surgical resection of chondrosarcoma is the only effective treatment, and no other treatment options including targeted therapies, conventional chemotherapies, or immunotherapies are available for these patients. Here, we identify a signal pathway way involving EZH2\/SULF1\/cMET axis that contributes to malignancy of chondrosarcoma and provides a potential therapeutic option for the disease. A non-biased chromatin immunoprecipitation sequence, cDNA microarray analysis, and validation of chondrosarcoma cell lines identified sulfatase 1 (\n                    <jats:italic>SULF1<\/jats:italic>\n                    ) as the top EZH2-targeted gene to regulate chondrosarcoma progression. Overexpressed EZH2 resulted in downregulation of SULF1 in chondrosarcoma cell lines, which in turn activated cMET pathway. Pharmaceutical inhibition of cMET or genetically silenced cMET pathway significantly retards the chondrosarcoma growth and extends mice survival. The regulation of EZH2\/SULF1\/cMET axis were further validated in patient samples with chondrosarcoma. The results not only established a signal pathway promoting malignancy of chondrosarcoma but also provided a therapeutic potential for further development of effective target therapy to treat chondrosarcoma.\n                  <\/jats:p>","DOI":"10.7554\/elife.79432","type":"journal-article","created":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T06:15:20Z","timestamp":1671776120000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.79432","source":"Crossref","is-referenced-by-count":10,"title":["EZH2\/hSULF1 axis mediates receptor tyrosine kinase signaling to shape cartilage tumor progression"],"prefix":"10.7554","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3365-1240","authenticated-orcid":true,"given":"Zong-Shin","family":"Lin","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/00v408z34","id-type":"ROR","asserted-by":"publisher"}],"name":"Graduate Institute of Biomedical Sciences, College of Medicine, China Medical 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