For sufferers with tumors expressing REST target genes at near typical and mid selection ranges, the administration Cabozantinib of four or far more rounds of chemotherapy is associated with a statistically important raise in sickness free of charge survival in excess of individuals who underwent 3 or fewer doses of chemotherapy. For patients with REM tumors, on the other hand, the improve in survival time related with higher dose chemo treatment was not statistically considerable. To uncover probable mechanisms behind the differential ailment program and response to treatment method observed in REM tumors we searched for glioma linked tumor suppres sor genes whose mRNA expression amounts co varied with REST signature genes. From the recognized glioma tumor suppressor genes, 4 had conserved REST binding web-sites, neurofibromin one, brain expressed X linked 1, cyclin dependent kinase inhibitor 1B and miR 124.
NF1 is really a Ras GTPase activating protein and its perform is regarded for being misplaced in gliomas through mutation or degradation. Lately pub lished ChIP ChIP information examining REST bound genes in glial cells located that REST immediately binds NF1 endoge nously in mouse oligodendrocytes, suggesting that NF1 can be a direct target of REST repression. Our perform suggests that aberrant repression by REST may possibly be an additional route to loss of NF1 in gliomas. BEX1 can be a glioma tumor suppressor gene, the overex pression of which correctly suppresses human glioma xenograft tumor growth in nude mice. BEX1 mRNA expression is lost quite a few gliomas, in element by way of promoter methylation.
Published ChIP Seq evaluation for REST bound genes uncovered that REST straight binds the BEX1 gene in Jurkat T cells, suggesting that it too is surely an endogenous REST target. BEX1 mRNA displays a strong correlation with REST signature gene expression and it is two fold reduced in REM tumors than near usual tumors, sug gesting the lowered BEX1 expression observed in these tumors may possibly be because of elevated REST perform. p27KIP1 is a cyclin dependent kinase inhibitor that regu lates the G1 S transition by inhibiting numerous CDK complexes, which include CDK2 and CDK4. Decreased ex pression of p27KIP1 in astrocytomas is associated with enhanced proliferation, and decreased patient survival. p27KIP1 mRNA levels in tumors correlate with REST signature gene expression and its gene con tains a consensus REST binding internet site, suggesting the lowered p27KIP1 expression observed in these tumors may possibly be as a result of enhanced REST perform.
Interestingly, loss of NF1, p27KIP1 and BEX1 are all asso ciated with glioma chemotherapy resistance, suggesting that these genes may perhaps play a role in the decreased advantage of large dose chemotherapy in patients with REM tumors. Here, we've offered evidence that REST perform is elevated in glioma tumors and that this heightened exercise correlates with differential tumor aggressiveness and response to treatment method.