TY - JOUR
T1 - Brd4-bound enhancers drive cell-intrinsic sex differences in glioblastoma
AU - Kfoury, Najla
AU - Qi, Zongtai
AU - Prager, Briana C.
AU - Wilkinson, Michael N.
AU - Broestl, Lauren
AU - Berrett, Kristopher C.
AU - Moudgil, Arnav
AU - Sankararaman, Sumithra
AU - Chen, Xuhua
AU - Gertz, Jason
AU - Rich, Jeremy N.
AU - Mitra, Robi D.
AU - Rubin, Joshua B.
N1 - Funding Information:
This work was supported by NIH Grants RO1 CA174737 (J.B.R.), RF1MH117070, U01MH109133 (National Institute of Mental Health) (R.D.M.), R01GM123203 (National Institute of General Medical Sciences) (R.D.M.), and R21 HG009750 (National Human Genome Research Institute) (R.D.M.); Joshua's Great Things (J.B.R.); The Children's Discovery Institute (J.B.R. and R.D.M.); and NIH Grants T32GM007200, T32HG000045, and F30HG009986 (A.M.). We thank the Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine for help with genomic analysis. The Center is partially supported by National Cancer Institute Cancer Center Support Grant No. P30 CA91842 to the Siteman Cancer Center and by Institute of Clinical and Translational Sciences/Clinical and Translational Sciences Award Grant No. UL1 TR000448 from the National Center for Research Resources (NCRR), a component of the NIH, and NIH Roadmap for Medical Research. This publication is solely the responsibility of the authors and does not necessarily represent the official view of the NCRR or NIH.
Funding Information:
ACKNOWLEDGMENTS. This work was supported by NIH Grants RO1 CA174737 (J.B.R.), RF1MH117070, U01MH109133 (National Institute of Mental Health) (R.D.M.), R01GM123203 (National Institute of General Medical Sciences) (R.D.M.), and R21 HG009750 (National Human Genome Research Institute) (R.D.M.); Joshua’s Great Things (J.B.R.); The Children’s Discovery Institute (J.B.R. and R.D.M.); and NIH Grants T32GM007200, T32HG000045, and F30HG009986 (A.M.). We thank the Genome Technology Access Center in the Department of Genetics at Washington University School of Medicine for help with genomic analysis. The Center is partially supported by National Cancer Institute Cancer Center Support Grant No. P30 CA91842 to the Siteman Cancer Center and by Institute of Clinical and Translational Sciences/Clinical and Translational Sciences Award Grant No. UL1 TR000448 from the National Center for Research Resources (NCRR), a component of the NIH, and NIH Roadmap for Medical Research. This publication is solely the responsibility of the authors and does not necessarily represent the official view of the NCRR or NIH.
Publisher Copyright:
© This open access article is distributed under Creative Commons Attribution-NonCommercialNoDerivatives License 4.0 (CC BY-NC-ND).
PY - 2021/4/20
Y1 - 2021/4/20
N2 - Sex can be an important determinant of cancer phenotype, and exploring sex-biased tumor biology holds promise for identifying novel therapeutic targets and new approaches to cancer treatment. In an established isogenic murine model of glioblastoma (GBM), we discovered correlated transcriptome-wide sex differences in gene expression, H3K27ac marks, large Brd4-bound enhancer usage, and Brd4 localization to Myc and p53 genomic binding sites. These sex-biased gene expression patterns were also evident in human glioblastoma stem cells (GSCs). These observations led us to hypothesize that Brd4-bound enhancers might underlie sex differences in stem cell function and tumorigenicity in GBM. We found that male and female GBM cells exhibited sex-specific responses to pharmacological or genetic inhibition of Brd4. Brd4 knockdown or pharmacologic inhibition decreased male GBM cell clonogenicity and in vivo tumorigenesis while increasing both in female GBM cells. These results were validated in male and female patient-derived GBM cell lines. Furthermore, analysis of the Cancer Therapeutic Response Portal of human GBM samples segregated by sex revealed that male GBM cells are significantly more sensitive to BET (bromodomain and extraterminal) inhibitors than are female cells. Thus, Brd4 activity is revealed to drive sex differences in stem cell and tumorigenic phenotypes, which can be abrogated by sex-specific responses to BET inhibition. This has important implications for the clinical evaluation and use of BET inhibitors.
AB - Sex can be an important determinant of cancer phenotype, and exploring sex-biased tumor biology holds promise for identifying novel therapeutic targets and new approaches to cancer treatment. In an established isogenic murine model of glioblastoma (GBM), we discovered correlated transcriptome-wide sex differences in gene expression, H3K27ac marks, large Brd4-bound enhancer usage, and Brd4 localization to Myc and p53 genomic binding sites. These sex-biased gene expression patterns were also evident in human glioblastoma stem cells (GSCs). These observations led us to hypothesize that Brd4-bound enhancers might underlie sex differences in stem cell function and tumorigenicity in GBM. We found that male and female GBM cells exhibited sex-specific responses to pharmacological or genetic inhibition of Brd4. Brd4 knockdown or pharmacologic inhibition decreased male GBM cell clonogenicity and in vivo tumorigenesis while increasing both in female GBM cells. These results were validated in male and female patient-derived GBM cell lines. Furthermore, analysis of the Cancer Therapeutic Response Portal of human GBM samples segregated by sex revealed that male GBM cells are significantly more sensitive to BET (bromodomain and extraterminal) inhibitors than are female cells. Thus, Brd4 activity is revealed to drive sex differences in stem cell and tumorigenic phenotypes, which can be abrogated by sex-specific responses to BET inhibition. This has important implications for the clinical evaluation and use of BET inhibitors.
KW - BET inhibitors
KW - Brd4-bound enhancers
KW - Glioblastoma
KW - Sex differences
KW - Sex-specific transcriptional programs
UR - http://www.scopus.com/inward/record.url?scp=85104288465&partnerID=8YFLogxK
U2 - 10.1073/pnas.2017148118
DO - 10.1073/pnas.2017148118
M3 - Article
C2 - 33850013
AN - SCOPUS:85104288465
SN - 0027-8424
VL - 118
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 16
M1 - e2017148118
ER -