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

44 Pages Posted: 8 Jul 2019 Sneak Peek Status: Review Complete

See all articles by Edgar Gonzalez-Buendia

Edgar Gonzalez-Buendia

Northwestern University - Department of Neurological Surgery

Junfei Zhao

Columbia University - Department of Systems Biology; Columbia University - Department of Biomedical Informatics

Lu Wang

Northwestern University, Feinberg School of Medicine, Department of Biochemistry & Molecular Genetics

Subhas Mukherjee

Northwestern University - Department of Pathology

Stacy A. Marshall

Northwestern University, Feinberg School of Medicine, Department of Biochemistry & Molecular Genetics

Eric Feldstein

Northwestern University - Department of Neurological Surgery

Daniel Zhang

Northwestern University - Department of Neurological Surgery

Catalina Lee-Chang

Northwestern University - Department of Neurological Surgery

Aayushi Mahajan

Columbia University - Department of Pathology and Cell Biology

Li Chen

Northwestern University - Department of Neurological Surgery

Ronald Realubit

Columbia University

Charles Karan

Columbia University

Lisa Magnuson

Northwestern University - Department of Neurological Surgery

Craig Horbinski

Northwestern University - Department of Neurological Surgery

Jann N. Sarkaria

Mayo Clinic

Ahmed Mohyeldin

Ohio State University (OSU)

Ichiro Nakano

University of Alabama

Charles D. James

Northwestern University - Department of Neurological Surgery

Daniel J. Brat

Northwestern University - Department of Pathology

Atique Ahmed

Northwestern University - Department of Neurological Surgery

Peter Canoll

Columbia University - Department of Pathology and Cell Biology

Raul Rabadan

Columbia University - Department of Systems Biology; Columbia University - Department of Biomedical Informatics

Ali Shilatifard

Northwestern University, Feinberg School of Medicine, Department of Biochemistry & Molecular Genetics

Adam M. Sonabend

Northwestern University - Department of Neurological Surgery

More...

Abstract

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

Suggested Citation

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). CANCER-CELL-D-19-00588. Available at SSRN: https://ssrn.com/abstract=3414699 or http://dx.doi.org/10.2139/ssrn.3414699
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Edgar Gonzalez-Buendia

Northwestern University - Department of Neurological Surgery

Chicago, IL 60611
United States

Junfei Zhao

Columbia University - Department of Systems Biology

College of Physicians and Surgeons
630 West 168th Street, 3rd Floor, Suite 3-470
New York, NY 10032
United States

Columbia University - Department of Biomedical Informatics

New York, NY 10032
United States

Lu Wang

Northwestern University, Feinberg School of Medicine, Department of Biochemistry & Molecular Genetics

Chicago, IL 60611
United States

Subhas Mukherjee

Northwestern University - Department of Pathology

Chicago, IL
United States

Stacy A. Marshall

Northwestern University, Feinberg School of Medicine, Department of Biochemistry & Molecular Genetics

Chicago, IL 60611
United States

Eric Feldstein

Northwestern University - Department of Neurological Surgery

Chicago, IL 60611
United States

Daniel Zhang

Northwestern University - Department of Neurological Surgery

Chicago, IL 60611
United States

Catalina Lee-Chang

Northwestern University - Department of Neurological Surgery

Chicago, IL 60611
United States

Aayushi Mahajan

Columbia University - Department of Pathology and Cell Biology

New York, NY 10032
United States

Li Chen

Northwestern University - Department of Neurological Surgery

Chicago, IL 60611
United States

Ronald Realubit

Columbia University

3022 Broadway
New York, NY 10027
United States

Charles Karan

Columbia University

3022 Broadway
New York, NY 10027
United States

Lisa Magnuson

Northwestern University - Department of Neurological Surgery

Chicago, IL 60611
United States

Craig Horbinski

Northwestern University - Department of Neurological Surgery

Chicago, IL 60611
United States

Jann N. Sarkaria

Mayo Clinic

200 First Street SW
Rochester, MN (507) 284-2511 55905
United States

Ahmed Mohyeldin

Ohio State University (OSU)

Blankenship Hall-2010
901 Woody Hayes Drive
Columbus, OH OH 43210
United States

Ichiro Nakano

University of Alabama

101 Paul W. Bryant Dr.
Box 870382
Tuscaloosa, AL 35487
United States

Charles D. James

Northwestern University - Department of Neurological Surgery

Chicago, IL 60611
United States

Daniel J. Brat

Northwestern University - Department of Pathology

Chicago, IL
United States

Atique Ahmed

Northwestern University - Department of Neurological Surgery

Chicago, IL 60611
United States

Peter Canoll

Columbia University - Department of Pathology and Cell Biology

New York, NY 10032
United States

Raul Rabadan

Columbia University - Department of Systems Biology

College of Physicians and Surgeons
630 West 168th Street, 3rd Floor, Suite 3-470
New York, NY 10032
United States

Columbia University - Department of Biomedical Informatics

3022 Broadway
New York, NY 10027
United States

Ali Shilatifard

Northwestern University, Feinberg School of Medicine, Department of Biochemistry & Molecular Genetics ( email )

Chicago, IL 60611
United States

Adam M. Sonabend (Contact Author)

Northwestern University - Department of Neurological Surgery ( email )

Chicago, IL 60611
United States

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