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BMI-1 is a transcriptional repressor and overexpresses in various human cancer tissues, which is also known to involve in the maintenance of “stem cell” features in a cell sub-population within the tumor. Here, we investigate the roles of BMI1 oncogene in brain tumors, notably involving drug-resistant metabolism. Interestingly, microarray datasets in OMCOMINE indicated that BMI1 is not commonly increased in clinical brain tumors, and survival plots in PROGgeneV2 also showed that BMI1 expression is not statistically associated with glioma patients. However, stressful serum starvation and anchorage independence growth conditions enabled to induce upregulation of BMI1. Further investigation, we identified HDAC-Sp1 is a stress-responsive pathway, critically promoting BMI1 expression. HDAC inhibition via vorinostat treatment prevented the binding of Sp1 to BMI1 promoter, leading to decreased BMI1 expression and attenuated tumor growth of TMZ-resistant glioma xenografts. Importantly, increased expression of the HDAC-Sp1-BMI1 axis but not BMI1 alone showed an increased risk of death in both high- and low-grade glioma. Thus, the HDAC-Sp1-BMI1 axis is critical to attenuate stress- and therapy-induced death in glioma cells and the axis inhibition may prevent the recurrence of malignant cells persisting after primary therapy.

CSIG-12. HDACs-Sp1-BMI1 PATHWAY IS INVOLVED IN THE ATTENUATION OF STRESS- AND THERAPY-INDUCED DEATH IN GLIOMA