It is known that many types of cancer in men and women have markedly different incidence rates and very different outcomes. Among these are brain tumors, the most common of which are glioblastomas (GBM). These are the most aggressive tumors of the brain and occur at 60% higher rates in men, whether humans or not. Now, an amazing new study published in November 2020 on the preprint server bioRxiv * shows these differences to a gene called Brd4, a transcriptome-wide regulator of gene expression.
It has recently been recognized that susceptibility to disease and clinical phenotype are determined not only by pathogenic and environmental factors, but also by the sex of the patient. This also applies to lifestyle diseases, including metabolic diseases such as cardiovascular and neurological diseases, and cancer.
Gender specific GBM biology
The new study looked at differences in GBM biology in men and women to better understand the underlying factors and pathways that determine the risk and course of tumors. Previously, the researchers found that GBM cells in male mice are more susceptible to carcinogenic events and the effects of chemotherapy. Half of these differences have been confirmed in human GBM.
A later study showed that differences in survival in treated human GBM patients were due to the underlying transcription programs, which, as with normal sexual differentiation, were modulated by gender-specific epigenetic changes.
Brd4 and epigenetic modulation
The BET family of proteins is involved in the regulation of transcription through epigenetic reading and works with target genes for which they recruit specific transcription complexes. Brd4 is a BET protein that reads the acetylated histones H3 and H4 throughout the cell cycle and specifies its cell identity.
The enhancers tied to it may therefore be responsible for the fundamental gender differences in GBM. In addition, Brd4 inhibition is increasingly being attacked by drugs that epigenetically modulate growth in many cancers. It is unregulated in many types of cancer. It improves many processes such as the transition from epithelium to mesenchyme, conversion to a stem cell-like profile, and pluripotency.
Sex-dependent Brd4-linked enhancers
The current study shows that the gender differences in tumor phenotype vary with the effect of the Brd4-bound enhancer regulation molecule on the course of stem cell-like differentiation in male and female GBM cells. The inhibition of Brd4 by genetic and pharmacological factors also varies in men and women both in vivo and in vitro. Therefore, GBM cells are less likely to form new clones in males, and tumors are less likely to grow after Brd4 inhibition. The opposite occurs in female cells and tumors.
The researchers found that Brd4 binding sites were in regions with a high density of H3 acetylation. Of the Brd4-bound enhancers, one fifth (about 2,800) bound more Brd4 in males, while the same proportion bound more protein in female GBM cells. Of the former, 0.13% were on the Y chromosome and 3.11% on the X chromosome. Of the latter, 4.29% were on the X chromosome. The researchers comment: "The observed differences in Brd4-bound enhancers are not simply due to the different accumulation of Brd4 enhancers on sex chromosomes." In fact, this is the first time the use of Brd4-linked enhancers has been demonstrated with male and female bias in each cell type.
The researchers also found that Brd4-linked genes were regulated differently in men and women; In around 1,300 genes, around 52% were expressed more frequently in men. The pathways most frequently regulated by these genes include nuclear cancer pathways, which are therefore regulated differently in the sexes. Not only do the transcription programs that lead to tumor formation differ between men and women, but their binding by Brd4 enhancers also depends on gender.
Response to BET inhibitors
The response to low molecular weight inhibitors of BET proteins in male GBM cells was with a reduced clonogenic cell frequency, but increased in women. That is, the sex differences were reduced by Brd4 inhibition due to the responses occurring in opposite directions. The drugs reduced tumor growth in men, but increased it in women.
The authors point out: "These results show for the first time that the gender differences in the tumorigenic phenotype that we observe in our murine GBM cells are mediated by differential Brd4-linked enhancers and that the response to BET inhibition is sex-dependent . "
Similar results were later obtained with human GBM cells. Thus, not only the biology of these tumors, but also their response to therapeutic drugs is sex-dependent.
Previous studies showed that women with ER-positive breast or endometrial cancer had poor survival if Brd4 expression was low, but in men with prostate cancer, the same marker indicated better survival.
Transcription factors involved in oncogenesis and stem cell-like development were enriched for male biased Brd4-linked enhancers, but female biased Brd4-linked enhancers were linked to tumor suppressor genes such as p53. Thus, this gene is apparently able to promote tumor formation in male GBM, but suppress it in female GBD.
More studies are needed to understand the major transcriptional regulators that bind directly or indirectly to Brd4 to determine where it is found in the genome. However, the study showed that Brd4 is found in male and female GBM cells in the same location as Myc and p53.
The authors conclude: “We have identified sex-dependent Brd4-regulated genes and signaling pathways that could translate into new and promising therapeutic targets to improve survival for all GBM patients and potentially other cancers that have significant sex-specific differences in incidence or show result. "
* Important NOTE
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore should not be considered conclusive, guide clinical practice / health-related behavior, or be treated as established information.