Sonic Hedgehog (SHH) MB samples were clustered based on expression of LSD1 and LSD1-associated RE-1 silencing transcription factor (REST) target genes as well as genes involved in metastasis.
Dysregulation of repressor-element 1 silencing transcription factor REST/NRSF is related to several neuropathies, including medulloblastoma, glioblastoma, Huntington's disease, and neuropathic pain.
Genome-wide expression analyses and binding experiments indicate that Brg1 specifically coordinates with key transcription factors including Gli1, Atoh1 and REST to regulate the expression of both oncogenes and tumor suppressors that are required for medulloblastoma identity and proliferation.
In cancer biology, REST has been shown to play a tumor suppressor activity in epithelial cancers but an oncogenic role in brain childhood malignancies such as neuroblastoma and medulloblastoma.
Overexpression of REST is frequently found in human medulloblastomas and neuroblastomas, in which it is thought to maintain the stem character of tumour cells.
Since REST is located at 4q12, a chromosome region implicated in brain tumorigenesis, we conducted gene copy number analyses in medulloblastomas and gliomas.
To determine whether c-Myc and REST/NRSF act together to cause medulloblastomas, we used a previously established cell line derived from external granule layer stem cells transduced with activated c-myc (NSC-M).
To determine whether c-Myc and REST/NRSF act together to cause medulloblastomas, we used a previously established cell line derived from external granule layer stem cells transduced with activated c-myc (NSC-M).
To determine whether countering REST/NRSF activity blocks tumorigenicity of medulloblastoma cells, especially in the intracranial (i.c.) environment, we found that adenovirus-mediated expression of REST-VP16, a recombinant transcription factor that can compete with REST/NRSF and activate REST/NRSF target genes instead of repressing them, blocked the i.c. tumorigenic potential of medulloblastoma cells and inhibited growth of established tumors in nude mice, suggesting that REST/NRSF may serve as a therapeutic target for medulloblastoma and that forced expression of neuronal differentiation genes in medulloblastoma cells through agents, such as REST-VP16, can interfere with their tumorigenicity.
To determine whether countering REST/NRSF activity blocks tumorigenicity of medulloblastoma cells, especially in the intracranial (i.c.) environment, we found that adenovirus-mediated expression of REST-VP16, a recombinant transcription factor that can compete with REST/NRSF and activate REST/NRSF target genes instead of repressing them, blocked the i.c. tumorigenic potential of medulloblastoma cells and inhibited growth of established tumors in nude mice, suggesting that REST/NRSF may serve as a therapeutic target for medulloblastoma and that forced expression of neuronal differentiation genes in medulloblastoma cells through agents, such as REST-VP16, can interfere with their tumorigenicity.