Brd4-bound enhancers drive cell-intrinsic sex differences in glioblastoma
Menée in vitro et à l'aide d'un modèle murin de glioblastome, cette étude met en évidence le rôle des régions amplificatrices de l'ADN liées à la kinase Brd4 dans la survenue de différences sexuelles au niveau de la fonction et de la tumorigénicité des cellules souches cancéreuses
Résumé en anglais
Consistent sex differences in incidence and outcome have been reported in numerous cancers including brain tumors. GBM, the most common and aggressive primary brain tumor, occurs with higher incidence and shorter survival in males compared to females. Brd4 is essential for regulating transcriptome-wide gene expression and specifying cell identity, including that of GBM. We report that sex-biased Brd4 activity drives sex differences in GBM and renders male and female tumor cells differentially sensitive to BET inhibitors. The observed sex differences in BETi treatment strongly indicate that sex differences in disease biology translate into sex differences in therapeutic responses. This has critical implications for clinical use of BET inhibitors further affirming the importance of inclusion of sex as a biological variable.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.All raw data and processed files have been deposited in the Short Read Archive/Gene Expression Omnibus database (https://www.ncbi.nlm.nih.gov/geo/). GSE156821 is the reference series for all data. The SubSeries that are linked to GSE156821 are GSE156678, GSE156819, and GSE156820. Source code for the python package used to map calling card reads and call peaks can found in GitLab at https://gitlab.com/rob.mitra/mammalian_cc_tools (see README_CCFTOOLS.pdf in the ccf tools directory).
