For patients with tumors expressing REST target genes at near typical and mid selection amounts, the administration inhibitor Decitabine of four or much more rounds of chemotherapy is related that has a statistically considerable increase in illness no cost survival over individuals who underwent 3 or fewer doses of chemotherapy. For individuals with REM tumors, having said that, the maximize in survival time linked with substantial dose chemo treatment was not statistically major. To uncover attainable mechanisms behind the differential disorder course and response to treatment method observed in REM tumors we searched for glioma connected tumor suppres sor genes whose mRNA expression amounts co varied with REST signature genes. Of your recognized glioma tumor suppressor genes, 4 had conserved REST binding websites, neurofibromin one, brain expressed X linked 1, cyclin dependent kinase inhibitor 1B and miR 124.
NF1 is a Ras GTPase activating protein and its function is acknowledged to be lost in gliomas by mutation or degradation. Recently pub lished ChIP ChIP data examining REST bound genes in glial cells uncovered that REST right binds NF1 endoge nously in mouse oligodendrocytes, suggesting that NF1 is often a direct target of REST repression. Our perform suggests that aberrant repression by REST may perhaps be yet another route to reduction of NF1 in gliomas. BEX1 is usually a glioma tumor suppressor gene, the overex pression of which properly suppresses human glioma xenograft tumor development in nude mice. BEX1 mRNA expression is misplaced quite a few gliomas, in component as a result of promoter methylation.
Published ChIP Seq examination for REST bound genes observed that REST directly binds the BEX1 gene in Jurkat T cells, suggesting that it too is definitely an endogenous REST target. BEX1 mRNA demonstrates a strong correlation with REST signature gene expression and it is two fold reduce in REM tumors than close to usual tumors, sug gesting that the decreased BEX1 expression observed in these tumors could be on account of greater REST perform. p27KIP1 is really a cyclin dependent kinase inhibitor that regu lates the G1 S transition by inhibiting quite a few CDK complexes, together with CDK2 and CDK4. Decreased ex pression of p27KIP1 in astrocytomas is related with enhanced proliferation, and decreased patient survival. p27KIP1 mRNA ranges in tumors correlate with REST signature gene expression and its gene con tains a consensus REST binding web site, suggesting that the reduced p27KIP1 expression observed in these tumors might be because of elevated REST perform.
Interestingly, reduction of NF1, p27KIP1 and BEX1 are all asso ciated with glioma chemotherapy resistance, suggesting that these genes may perform a purpose from the reduced benefit of higher dose chemotherapy in patients with REM tumors. Right here, we have now offered evidence that REST function is increased in glioma tumors and that this heightened action correlates with differential tumor aggressiveness and response to treatment.