Bcl6 Modulates The Tp53 And Stat Pathways In Glioma

Glioblastoma multiforme (GBM) remains the most aggressive brain malignancy with little improvement in prognosis or therapy for decades. Recently, we identified BCL6, also known as ZBTB27, to be a novel oncogene in GBM. In this study, we performed IHC analysis of 153 primary human glioma specimens and 8 normal brain samples. BCL6 expression is robustly elevated in tumor samples and positively correlated with glioma pathological grade. High BCL6 expression strongly predicts a worse prognosis of GBM patients. Depletion of BCL6 in human GBM cells reduced the incorporation of BrdU, promoted the cellular senescence and inhibited the growth of human GBM cells in vivo. Next, genome-wide occupancy of BCL6 in GBM cells was characterized by ChIP-seq assay. Genomic regions centered on BCL6 peaks are co-enriched with RNA-Pol II and flanked with strong H3K27ac and H3K4me3 modifications. MYC and two long non-coding RNAs MALAT1 and NEAT1 were identified as novel BCL6 targets in GBM. Moreover, pathway enrichment analysis of BCL6 peak-associated genes reveals a significant enrichment of JAK-STAT, TP53, ERBB and MAPK pathways. We demostrated further that BCL6 represses the TP53 pathway and promotes the JAK-STAT pathway activation in GBM cells. Together, our findings uncover potential downstream targets and provide a better understanding of BCL6 function in GBM. Citation Format: Ye Chen, Liang Xu, Marina Dutra-Clarke, Anand Mayakonda, De-Chen Lin, Lynnette Koh, Yuk Kien Chong, Edwin Sandanaraj, Vikas Madan, Henry Yang, Ngan Doan, Jonathan W. Said, William H. Yong, Markus Muschen, Beng Ti Ang, Carol Tang, Joshua J. Breunig, Phillip Koeffler. BCL6 modulates the TP53 and STAT pathways in glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1524. doi:10.1158/1538-7445.AM2017-1524