TOP2B Enzymatic Activity on Promoters and Introns Modulates Multiple Oncogenes in Human Gliomas

Edgar Gonzalez-Buendia, Junfei Zhao, Lu Wang, Subhas Mukherjee, Daniel Zhang, Víctor A. Arrieta, Eric Feldstein, J. Robert Kane, Seong Jae Kang, Catalina Lee-Chang, Aayushi Mahajan, Li Chen, Ronald Realubit, Charles Karan, Lisa Magnuson, Craig Horbinski, Stacy A. Marshall, Jann N. Sarkaria, Ahmed Mohyeldin, Ichiro NakanoMukesh Bansal, Charles D. James, Daniel J. Brat, Atique Ahmed, Peter Canoll, Raul Rabadan, Ali Shilatifard, Adam M. Sonabend

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: The epigenetic mechanisms involved in transcriptional regulation leading to malignant phenotype in gliomas remains poorly understood. Topoisomerase IIB (TOP2B), an enzyme that decoils and releases torsional forces in DNA, is overexpressed in a subset of gliomas. Therefore, we investigated its role in epigenetic regulation in these tumors. Experimental Design: To investigate the role of TOP2B in epigenetic regulation in gliomas, we performed paired chromatin immunoprecipitation sequencing for TOP2B and RNA-sequencing analysis of glioma cell lines with and without TOP2B inhibition and in human glioma specimens. These experiments were complemented with assay for transposase-accessible chromatin using sequencing, gene silencing, and mouse xenograft experiments to investigate the function of TOP2B and its role in glioma phenotypes. Results: We discovered that TOP2B modulates transcription of multiple oncogenes in human gliomas. TOP2B regulated transcription only at sites where it was enzymatically active, but not at all native binding sites. In particular, TOP2B activity localized in enhancers, promoters, and introns of PDGFRA and MYC, facilitating their expression. TOP2B levels and genomic localization was associated with PDGFRA and MYC expression across glioma specimens, which was not seen in nontumoral human brain tissue. In vivo, TOP2B knockdown of human glioma intracranial implants prolonged survival and downregulated PDGFRA. Conclusions: Our results indicate that TOP2B activity exerts a pleiotropic role in transcriptional regulation of oncogenes in a subset of gliomas promoting a proliferative phenotype.

Original languageEnglish (US)
Pages (from-to)5669-5680
Number of pages12
JournalClinical Cancer Research
Volume27
Issue number20
DOIs
StatePublished - Oct 15 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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