New publications for NCMM’s Prostate Cancer Group

Two papers have recently been published by NCMM’s Prostate Cancer Research Group. 

image of prostate cancer cells

c-Myc (pink areas) and PSA (brown areas) expression in prostate cancer specimens. Cells with high expression of c-Myc present  no PSA expression, and vice versa. Image from Barfeld, Urbanucci et al. 

The publications have appeared in EBiomedicine and BMC Genomics. Here, we take a quick look at the findings behind each publication:

Paper one: EBiomedicineStudy could help to understand why certain biomarkers fail to drive a more personalised treatment for prostate cancer

Prostate cancer is the second most common cause of cancer death in men in the developed world. Since the 1990s, early detection methods, such as screening for PSA (prostate-specific antigen) have been used to stratify patients at risk of death due to prostate cancer.

Whilst screening for prostate cancer can detect the disease early, it is also controversial. The standard screening process is unable to determine how aggressive the tumour is going to be, or what type and degree of treatment is needed. This means that men diagnosed with prostate cancer may end up receiving far more treatment, and further invasive testing, than is really needed for their cancer; all of which can have a very negative effect on the patient’s quality of life.

Discovery that may help improve the screening process

Research by NCMM’s Prostate Cancer Group led by Professor Ian G. Mills is focusing, amongst other things, on exploring what other potential biomarkers could be used to assess the severity of prostate cancer in individual patients.

The research, carried out by Dr Barfeld and Dr Urbanucci et al, studied the interplay between two important oncogenic transcription factors and therapeutic drug targets; the androgen receptor (AR), which is currently the main target for prostate cancer treatment, and c-Myc, a ‘master regulator’ oncogene that processes cellular growth regulation and cellular metabolism. Although c-Myc is known to be commonly upregulated in prostate cancer, its impact on AR activity, and on prostate cancer biomarkers, is not well understood. 

Graphical abstract
Graphical Abstract: c-Myc antagonises the transcriptional activity of the androgen receptor in prostate cancer, affecting key gene networks. Illustration: Alfonso Urbanucci

The research found that c-Myc and the AR regulate the expression of important genes for prostate cancer progression. Importantly, many genes are commonly regulated by both c-Myc and AR. The key finding of this study is that c-Myc, which was generally thought to be a generalist amplifier of transcription, is instead able to antagonise the expression of some of these important genes, such as PSA. PSA is the well-known prostate cancer biomarker used in the clinic to diagnose and follow up prostate cancer patients.

c-MYC overexpression has been previously observed in prostate cancer. However, this is the first time that c-Myc has been shown to deregulate the transcriptional program promoted by the AR.

Insights for personalised medicine

These findings provide important insights that may have implications for personalised medicine. Namely, this study provides evidences for helping to determine why PSA or other biomarkers may fail to identify the right treatment for some patients.

Moreover, this study provides a better understanding of which biomarkers may be better for identifying the right treatments for patients on an individual basis.

The findings were recently published in EBiomedicine: Read the full article, c-Myc Antagonises the Transcriptional Activity of the Androgen Receptor in Prostate Cancer Affecting Key Gene Networks

The paper was also highlighted in Nature Reviews Urology: https://www.nature.com/nrurol/journal/vaop/ncurrent/full/nrurol.2017.62.html 

Paper two: BMC Genomics

Study evaluates how a generic epigenetic factor, BRD4, is able to flag areas of DNA that vary within individuals, and that are associated with several diseases

A second study led by Dr Urbanucci and Prof. Mills (Zuber et al), also in collaboration with the group of Prof. Ole Andreassen at the NORMENT school, sheds further light on the role of the epigenetic reader Bromodomain containing protein 4 (BRD4), and its capacity to annotate genetic variants that are of functional importance in cancer and other disease development.

Epigenetics and disease prediction

A patient’s risk of developing cancer can often be identified through the identification of DNA-sequence variants, such as single nucleotide polymorphisms (SNPs). SNPs can also help predict a patient’s response to a drug, or their susceptibility to environmental factors.

Interestingly, epigenetics – the study of heritable changes in gene activity that do not involve alterations to the genetic code – are proposed to be useful in helping to identify clinically relevant SNPs that are of functional importance in cancer development.

Super-enhancers are cell-specific DNA elements that act to determine tissue or cell identity and drive tumour progression. Although previous approaches have attempted to explain the risk associated with SNPs in regulatory DNA elements, so far epigenetic readers, such as BRD4 and super-enhancers have not been used to annotate SNPs. In prostate cancer, androgen receptor (AR) binding sites to chromatin, are so far the only read-out used to inform functional annotations of SNPs.

BRD4 key discriminant of tissue-specific enhancers

In this study, Urbanucci and colleagues demonstrate that BRD4 is the key discriminant of tissue-specific enhancers, and show that it is more powerful than other previously studied factors such as AR binding information to identify prostate cancer-specific risk loci.

Furthermore, the authors showed that this approach is applicable to other diseases and traits, such as breast cancer and schizophrenia.

Proteins responsible for reading epigenetic marks on gene expression are increasingly becoming a target for drug development. These proteins bind DNA areas, which function as regulatory elements for the expression of genes, similar to genetics switches. The sequence embedded in such genetic switches may vary from individual to individual. Some variation is associated with an increased risk of developing diseases such as cancer or, as shown in a study by Urbanucci and colleagues, neuropsychiatric disorders.

First time enrichment of particular DNA variations have been evaluated

This study, by Urbanucci and colleagues, focused on the epigenetic reader Bromodomain containing protein 4 (BRD4). For the first time, the authors were able to evaluate the enrichment of particular DNA variations associated with different diseases.

They were able to show this just by using the epigenetic readers BRD4 binding to the DNA as a flag in genome-wide association studies for prostate, breast and lung cancer, as well as in Schizophrenia. The study shows that this provides a powerful tool for prioritizing genetic risk DNA variants (SNPs, alias “single nucleotide polymorphisms”).

The findings were recently published in BMC Genomics.

Read the full article, Bromodomain protein 4 discriminates tissue-specific super-enhancers containing disease-specific susceptibility loci in prostate and breast cancer

Publication One: EBiomedicine

Publication Two: BMC Genomics

By Annabel Darby, Alfonso Urbanucci
Published June 13, 2017 4:32 PM - Last modified Feb. 18, 2021 1:59 PM