气候变化领域集成服务门户(CCPortal): Brd4-bound enhancers drive cell-intrinsic sex differences in glioblastoma

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DOI	10.1073/pnas.2017148118
	Brd4-bound enhancers drive cell-intrinsic sex differences in glioblastoma
	Kfoury N.; Qi Z.; Prager B.C.; Wilkinson M.N.; Broestl L.; Berrett K.C.; Moudgil A.; Sankararaman S.; Chen X.; Gertz J.; Rich J.N.; Mitra R.D.; Rubin J.B.
发表日期	2021
ISSN	00278424
卷号	118 期号:16
英文摘要	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. © This open access article is distributed under Creative Commons Attribution-NonCommercialNoDerivatives License 4.0 (CC BY-NC-ND).
英文关键词	BET inhibitors; Brd4-bound enhancers; Glioblastoma; Sex differences; Sex-specific transcriptional programs
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/179845
作者单位	Department of Pediatrics, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, United States; Department of Neurological Surgery, University of California San Diego, San Diego, CA 92037, United States; Department of Genetics, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, United States; Center for Genome Sciences and Systems Biology, Washington University in St. Louis, St. Louis, MO 63110, United States; Division of Regenerative Medicine, Department of Medicine, University of California San Diego, San Diego, CA 92037, United States; Cleveland Clinic Lerner College of Medicine, Cleveland, OH 44195, United States; Medical Scientist Training Program, School of Medicine, Washington University in St. Louis, St. Louis, MO 63110, United States; Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, United States; Department of Neurosciences, University of California San Diego, San Diego, CA 92037,...
推荐引用方式 GB/T 7714	Kfoury N.,Qi Z.,Prager B.C.,et al. Brd4-bound enhancers drive cell-intrinsic sex differences in glioblastoma[J],2021,118(16).
APA	Kfoury N..,Qi Z..,Prager B.C..,Wilkinson M.N..,Broestl L..,...&Rubin J.B..(2021).Brd4-bound enhancers drive cell-intrinsic sex differences in glioblastoma.Proceedings of the National Academy of Sciences of the United States of America,118(16).
MLA	Kfoury N.,et al."Brd4-bound enhancers drive cell-intrinsic sex differences in glioblastoma".Proceedings of the National Academy of Sciences of the United States of America 118.16(2021).