DRES-13. RETINOBLASTOMA BINDING PROTEIN 4 (RBBP4) INTERACTS WITH p300 TO REGULATE DNA REPAIR AND APOPTOSIS GENES IN GLIOBLASTOMA

摘要

Recently, we have demonstrated that RBBP4 interacts with p300 to regulate MGMT and the homologous recombination repair genes RAD51, EYA1 and FIGNL1 in glioblastoma (GBM) cells. To gain insight into the genes regulated by the RBBP4/p300 complex, we have extended the above findings by performing RNAseq in patient derived xenograft (PDX) GBM43 cells with shRNA knockdown of RBBP4 or p300 and a control non-specific targeting construct (NT). Overall, silencing RBBP4 and p300 altered the expression of 4,696 genes, with upregulation of 2,644 (57%) genes and downregulation of 2052 (43%) genes. A total of 719 (35%) were coordinately downregulated by silencing either RBBP4 or p300, suggesting that these genes may be controlled by the RBBP4/p300 complex. A total of 42 (6%) of the downregulated genes were classified as DNA damage repair (DDR) genes. Interestingly, 31 of these genes function in a network connecting multiple DDR pathways. Parallel ChIPseq revealed that RBBP4 or p300 silencing decreased H3K27Ac and/or H3K9Ac within promoters of 34 of these genes suggesting histone acetylation, perhaps by p300, as the key mechanism by which RBBP4/p300 regulates these DDR genes. Interestingly, silencing RBBP4 or p300 coordinately suppressed 131 genes involved in cell death and survival, and 33 of these genes are connected in a network known to regulate apoptosis in brain tumor cells, including BCL2, BIRC2, BIRC3 and MYC. Collectively, these findings suggest that the RBBP4/p300 complex plays a critical role not only in the repair of DNA damage but may also govern the ability of cells to undergo apoptotic cell death. Even though further studies are still in progress to link RBBP4/p300 with DDR and apoptosis, we conclude that this complex possibly controls multiple DDR and apoptotic pathways and manipulation of this complex could sensitize therapy in GBM and perhaps in other human cancers in general.