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EPCO-29. KLF5 IS REQUIRED FOR THE SEX-DIFFERENCES ACROSS MULTIPLE TUMORIGENIC PHENOTYPES IN PEDIATRIC GLIOBLASTOMA (GBM)


 High-grade glioblastoma (GBM) is a highly heterogeneous, malignant cancer with no cure to date. A sex-biased incidence and therapeutic response is reported (1) for GBM with a male to female incidence ratio of 1.6:1 and female patients having a 4-6 month survival advantage (2) compared to male patients. In our current work, we sought to determine the molecular basis for the sex-bias in incidence and therapeutic response using an isogenic murine model of GBM with dual loss of neurofibromin 1 (NF1) and P53 (DNP53) in astrocytes. Our model yielded GBM from the murine astrocytes in a sex-biased manner, with male GBM cells exhibiting a highly significant proliferative, migratory, in-vivo tumorigenicity, stem-cell enrichment rate and therapeutic resistance compared to female GBM cells. Using transposon calling cards, we mapped Brd4 enhancer usage across the genome in male, compared to female GBM cells and identified key transcription factors that differentially enriched at male-biased, compared to female-biased Brd4 bound enhancers. Interestingly, female-biased Brd4-bound enhancers were enriched for transcription factors with tumor suppressor roles including P53 and SMAD4, whereas male-biased Brd4-bound enhancers were enriched for transcription factors with oncogenic roles, including Oct4, MYC and KLF5. Genetic or chemical silencing of KLF5 reduced the tumorigenic potential in male GBM with rates of cellular proliferation, survival, migration and stem-cell frequency significantly reduced to levels that resemble female GBM. Using transposon calling cards, we mapped KLF5 genomic localization in male and female GBM cells and identified significant peaks that affiliated with differentially expressed genes between the sexes. Interestingly, genes induced by KLF5 in the male cells were affiliated with poor survival in patients with various cancers, whereas those induced by KLF5 in the female cells were affiliated with favorable prognosis. This signifies the need to explore molecular mechanisms by which KLF5 drives these sex differences in GBM.