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Targeting IL-11R/EZH2 signaling axis as a therapeutic strategy for osteosarcoma lung metastases
Eswaran Devarajan1, R Eric Davis2, Hannah C Beird3
1Department of Orthopaedic Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1448, Houston, TX, 77030, USA.
Abstract:
Lung metastases are the primary cause of death for osteosarcoma (OS) patients. We recently validated interleukin-11 receptor α (IL-11Rα) as a molecular target for the inhibition of OS lung metastases. Since there is no clinically approved antibody against this receptor, we sought to identify downstream targets that mediate the effects of IL-11Rα signaling. We used shRNA to deplete IL-11Rα from OS cells; as a complementary approach, we added IL-11 exogenously to OS cells. The resulting changes in gene expression identified EZH2 as a downstream candidate. This was confirmed by knockdown of IL-11Rα in OS cells, which led to increased expression of genes repressed by histone methyltransferase EZH2, including members of the WNT pathway, a known target pathway of EZH2. Exogenous IL-11 increased the global levels of histone H3 lysine 27 trimethylation, evidence of EZH2 activation. Treatment with the EZH2 inhibitor GSK126 significantly reduced in vitro proliferation and increased cell-cycle arrest and apoptosis, which were partially mediated through the WNT pathway. In vivo, treatment of an orthotopic nude mouse model of OS with GSK126 inhibited lung metastatic growth and prolonged survival. In addition, significantly shorter recurrence-free survival was seen in OS patients with high levels of EZH2 in their primary tumors (P < .05). This suggests that IL-11Rα promotes OS lung metastasis via activation of EZH2. Thus, blocking EZH2 activity may be an effective strategy for inhibiting OS lung metastasis and improving prognosis.
Insights
Interleukin-11 receptor alpha (IL-11Rα) signaling promotes osteosarcoma lung metastasis by activating EZH2. Inhibiting EZH2 with GSK126 reduced tumor growth and improved survival in mice and patients, suggesting a new therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metastasis
Background:
- Lung metastases are the main cause of death in osteosarcoma (OS) patients.
- Interleukin-11 receptor alpha (IL-11Rα) is a validated molecular target for inhibiting OS lung metastases.
- There is no clinically approved antibody against IL-11Rα, necessitating the identification of downstream targets.
Purpose of the Study:
- To identify downstream targets mediating IL-11Rα signaling in osteosarcoma.
- To investigate the role of EZH2 in IL-11Rα-driven osteosarcoma lung metastasis.
- To evaluate the therapeutic potential of EZH2 inhibition in osteosarcoma.
Main Methods:
- shRNA-mediated depletion of IL-11Rα and exogenous IL-11 treatment in OS cells.
- Gene expression analysis to identify downstream targets.
- Assessment of EZH2 activity via histone trimethylation.
- In vitro and in vivo efficacy studies using the EZH2 inhibitor GSK126.
- Correlation analysis of EZH2 levels with patient survival data.
Main Results:
- EZH2 was identified as a downstream target of IL-11Rα signaling.
- IL-11Rα knockdown increased expression of EZH2-repressed genes, including WNT pathway members.
- Exogenous IL-11 increased global histone H3 lysine 27 trimethylation, indicating EZH2 activation.
- GSK126 treatment reduced OS cell proliferation, induced cell-cycle arrest and apoptosis, and inhibited lung metastasis in mice.
- High EZH2 levels in primary tumors correlated with shorter recurrence-free survival in OS patients.
Conclusions:
- IL-11Rα signaling promotes osteosarcoma lung metastasis through EZH2 activation.
- Targeting EZH2 with inhibitors like GSK126 is a promising therapeutic strategy for osteosarcoma.
- EZH2 inhibition may improve prognosis for osteosarcoma patients by reducing lung metastasis.
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