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Published on: September 13, 2019
EHMT1 mediates cellular motility in embryonal rhabdomyosarcoma by activating SOX8 expression
Upasana Bajaj1, Dipanwita Das1, Jia Yu Leung1,2
1Department of Physiology, Healthy Longevity and NUS Centre for Cancer Research Translation Research Program, Yong Loo Lin School of Medicine, National University of Singapore (NUS), 2 Medical Drive, MD9, Singapore, 117593, Republic of Singapore.
Background:
Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma. When metastatic, survival of children with RMS is less than 20% and has remained unchanged over two decades. No targeted drug therapy is available for these cancers. Genomic analysis has revealed a low incidence of somatic mutations in RMS. Epigenetic modifiers thus play important roles in driving oncogenesis. In this study, we examined the role of EHMT1 in fusion- negative embryonal rhabdomyosarcoma (ERMS), the most frequent subtype of RMS.
Methods:
We performed transcriptomic and phenotypic analysis in vitro and in vivo using EHMT1 depleted cells as well as that of its target gene SOX8.
Results:
EHMT1 was found to enhance migration and invasion of ERMS cells in vitro and metastasis in vivo. SOX8, a transcription factor that has key roles in cellular motility was significantly decreased upon EHMT1 loss. Consistently, SOX8 depletion phenotypically mimicked EHMT1 loss. Moreover, RNA Sequencing of SOX8 depleted cells showed down regulation of several integrin genes. Mechanistically, EHMT1 was found to upregulate SOX8 via regulation of BRD4 expression, and consequently increased BRD4 occupancy at the SOX8 promoter.
Conclusion:
Our study reveals a novel EHMT1-SOX8 axis that mediates metastasis in ERMS.
Insights
EHMT1 promotes metastasis in embryonal rhabdomyosarcoma (ERMS) by upregulating SOX8. This EHMT1-SOX8 axis is a potential therapeutic target for pediatric soft tissue sarcoma.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma.
- Metastatic RMS has a poor prognosis with limited therapeutic options.
- Somatic mutations are infrequent, suggesting a role for epigenetic alterations.
Purpose of the Study:
- To investigate the role of EHMT1 in fusion-negative embryonal rhabdomyosarcoma (ERMS).
- To elucidate the molecular mechanisms by which EHMT1 influences ERMS progression.
Main Methods:
- Transcriptomic and phenotypic analysis of EHMT1-depleted ERMS cells in vitro and in vivo.
- Analysis of the target gene SOX8 and its role in EHMT1-mediated effects.
- RNA sequencing to identify downstream targets of SOX8.
Main Results:
- EHMT1 depletion reduced ERMS cell migration, invasion, and metastasis.
- EHMT1 loss led to decreased SOX8 expression, mimicking EHMT1 loss phenotypes.
- EHMT1 upregulates SOX8 via BRD4, increasing BRD4 occupancy at the SOX8 promoter.
- SOX8 depletion resulted in downregulation of integrin genes.
Conclusions:
- A novel EHMT1-SOX8 signaling axis drives metastasis in ERMS.
- This axis represents a potential therapeutic target for metastatic ERMS.
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