Oncogene expression varies across gliomas. We discovered that TOP2B modulates transcription and splicing of multiple oncogenes in Drosophila brain tumors and human gliomas. TOP2B regulated transcription at sites where it was active, but not where found natively binding. TOP2B activity localized in enhancers, promoters and introns of PDGFRA and MYC, facilitating their expression. TOP2B levels and genomic localization was associated with PDGFR and MYC expression across gliomas specimens. Susceptibility to MST-16, a TOP2 inhibitor drug, correlated with baseline PDGRA expression across glioma cell lines. Our results indicate that TOP2B activity exerts a pleiotropic role in transcriptional regulation of oncogenes in a subset of gliomas. Modulation of oncogenes by TOP2-targeting drugs is the basis for a personalized approach for cancer therapy.
Keywords: TOP2B, epigenetic, transcription, cancer therapy
Gonzalez-Buendia, Edgar and Zhao, Junfei and Wang, Lu and Mukherjee, Subhas and Marshall, Stacy A. and Feldstein, Eric and Zhang, Daniel and Lee-Chang, Catalina and Mahajan, Aayushi and Chen, Li and Realubit, Ronald and Karan, Charles and Magnuson, Lisa and Horbinski, Craig and Sarkaria, Jann N. and Mohyeldin, Ahmed and Nakano, Ichiro and James, Charles D. and Brat, Daniel J. and Ahmed, Atique and Canoll, Peter and Rabadan, Raul and Shilatifard, Ali and Sonabend, Adam M., TOP2B Enzymatic Activity on Promoters and Introns Modulates Multiple Oncogenes in Human Gliomas (July 4, 2019). Available at SSRN: https://ssrn.com/abstract=3414699 or http://dx.doi.org/10.2139/ssrn.3414699
This version of the paper has not been formally peer reviewed.
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