EZH2/hSULF1 axis mediates receptor tyrosine kinase signaling to shape cartilage tumor progression

  1. Zong-Shin Lin
  2. Chiao-Chen Chung
  3. Yu-Chia Liu
  4. Chu-Han Chang
  5. Hui-Chia Liu
  6. Yung-Yi Liang
  7. Teng-Le Huang
  8. Tsung-Ming Chen
  9. Che-Hsin Lee
  10. Chih-Hsin Tang
  11. Mien-Chie Hung
  12. Ya-Huey Chen

  • Curated by eLife

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    In this study, Hung et al. address the biology and therapy of chondrosarcoma. The authors provided high-quality data that uncovered a new signaling axis, EZH2/hSULF1/c-Met, that promotes chondrosarcoma growth and progress. The authors also reported evidence showing that c-Met inhibition may be a plausible treatment option for chondrosarcoma. The findings are novel and translational and are of interest to cancer biologists and oncologists.

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Abstract

Chondrosarcomas are primary cancers of cartilaginous tissue and capable of alteration to highly aggressive, metastatic, and treatment-refractory states, leading to a poor prognosis with a five-year survival rate at 11 months for dedifferentiated subtype. 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 ( SULF1 ) 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.

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  1. Version published to 10.7554/elife.79432 on eLife
  2. eLife

    eLife assessment

    In this study, Hung et al. address the biology and therapy of chondrosarcoma. The authors provided high-quality data that uncovered a new signaling axis, EZH2/hSULF1/c-Met, that promotes chondrosarcoma growth and progress. The authors also reported evidence showing that c-Met inhibition may be a plausible treatment option for chondrosarcoma. The findings are novel and translational and are of interest to cancer biologists and oncologists.

  3. eLife

    Reviewer #1 (Public Review):

    Chondrosarcoma is a rare and aggressive cancer type with a poor prognosis and lacks effective treatment options. Developing an effective strategy for targeting chondrosarcoma is therefore considered an unmet clinical need. The goal of this study is to provide the molecular basis for chondrosarcoma progression and identify a potential strategy/agent for targeting chondrosarcoma. The study reveals that EZH2/hSULF1/c-Met axis is a critical signaling pathway for chondrosarcoma and provides proof of principle evidence that targeting c-MET by pharmacological approaches is an effective strategy to suppress tumor growth in chondrosarcoma mouse models. The aims to be explored for the study are novel and have been well accomplished. The conclusions from this current study are well supported by the compelling and robust datasets using diverse approaches. The study not only reveals a novel insight into how chondrosarcoma progression occurs but also offers the potential strategy for targeting chondrosarcoma, hence significantly advancing the field.

  4. eLife

    Reviewer #2 (Public Review):

    In this manuscript, Lin et al. reveal a novel and fundamental discovery regarding the role of the EZH2/SULF1/cMET signaling pathway in regulating the disease progression of chondrosarcoma, a malignant cartilaginous bone tumor.

    The significant strengths of the manuscript include identifying the EZH2-targeted genes in chondrosarcoma using EZH2-chromatin immunoprecipitation sequencing (ChIP-seq) and cDNA microarray profiling, deciphering the role of the EZH2/SULF1/cMET signaling pathway in regulating the progression of chondrosarcoma, verifying the therapeutic significance of this pathway using clinically used specific EZH2 and cMET pharmacological inhibitors in vitro and in vivo (in mouse tumor models), and demonstrating the clinical significance of the SULF1/cMET pathway in chondrosarcoma.

    The significant weaknesses of the manuscript appear not noted. A minor drawback seems associated with the manuscript presentation.

    In summary, I believe this manuscript's data well justify the authors' claims and conclusions, and this paper will significantly impact the field.

  5. Version published to 10.1101/2022.06.07.495151v1 on bioRxiv