Regulation of USP37 Expression by REST-Associated G9a-Dependent Histone Methylation
Tara H W Dobson1, Rashieda J Hatcher1, Jyothishmathi Swaminathan1
1Department of Pediatrics, University of Texas, MD Anderson Cancer Center, Houston, Texas.
Molecular Cancer Research : MCR
|May 10, 2017
Summary
The deubiquitylase USP37 suppresses medulloblastoma growth. REST and G9a histone methyltransferase repress USP37 by modifying histone H3K9, offering therapeutic potential in medulloblastoma treatment.
Area of Science:
- Oncology
- Molecular Biology
- Epigenetics
Background:
- USP37 (deubiquitylase) regulates cell proliferation via CDKN1B/p27Kip1 stability.
- USP37 expression is reduced in human medulloblastoma.
- USP37 exhibits tumor-suppressive properties in medulloblastoma.
Purpose of the Study:
- Investigate the mechanism of USP37 loss in medulloblastoma.
- Determine the role of REST and G9a in USP37 gene repression.
- Explore therapeutic potential of targeting this pathway.
Main Methods:
- Utilized mouse orthotopic models to assess USP37's tumor-suppressive function.
- Employed genetic and pharmacologic approaches to study G9a's role.
- Analyzed isogenic medulloblastoma cells with varying REST levels.
Main Results:
- USP37 prevents medulloblastoma growth in vivo.
- REST transcriptionally represses USP37.
- G9a (histone methyltransferase) mediates H3K9 methylation at the USP37 promoter, inhibiting its expression.
- G9a inhibition reduced medulloblastoma cell tumorigenicity.
- REST-dependent elevation of G9a activity correlates with decreased USP37 expression.
Conclusions:
- REST-associated G9a and H3K9 methylation repress USP37 expression in medulloblastoma.
- Reactivating USP37 via G9a inhibition shows therapeutic promise for REST-expressing medulloblastomas.
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