Brd4-bound enhancers drive cell-intrinsic sex differences in glioblastoma.

in Proceedings of the National Academy of Sciences of the United States of America by Najla Kfoury, Zongtai Qi, Briana C Prager, Michael N Wilkinson, Lauren Broestl, Kristopher C Berrett, Arnav Moudgil, Sumithra Sankararaman, Xuhua Chen, Jason Gertz, Jeremy N Rich, Robi D Mitra, Joshua B Rubin

TLDR

  • The study reveals sex-biased tumor biology in GBM and identifies Brd4 as a key driver of sex differences in stem cell and tumorigenic phenotypes.

Abstract

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.

Overview

  • The study investigates sex-biased tumor biology in an isogenic murine model of glioblastoma (GBM) and human glioblastoma stem cells (GSCs).
  • The researchers examine sex-specific expression of genes, histone marks, enhancer usage, and Brd4 localization to genomic binding sites.
  • The study aims to identify novel therapeutic targets and new approaches to cancer treatment by understanding sex-specific responses to bromodomain and extraterminal (BET) inhibitors.

Comparative Analysis & Findings

  • The study finds 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.
  • Sex-biased gene expression patterns are also observed in human GSCs.
  • Brd4 knockdown or pharmacologic inhibition decreases male GBM cell clonogenicity and in vivo tumorigenesis while increasing both in female GBM cells.

Implications and Future Directions

  • The study suggests that sex differences in stem cell and tumorigenic phenotypes can be abrogated by sex-specific responses to BET inhibition.
  • This has important implications for the clinical evaluation and use of BET inhibitors.
  • Future studies should investigate the clinical significance of sex-specific responses to BET inhibitors in GBM patients.
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