A recent news post on an exciting breakthrough in prostate cancer, which appeared this month of November 2016, piqued my interest since the subject was close to the research I worked on myself as a postdoctoral researcher.
I worked on deciphering the types of genes that were altered in prostate cancer in the presence or absence of the androgen hormone. Of course, I was concerned with picking out a few relevant genes and working on them individually rather than deciphering the signaling pathway involved.
And so, coming to the relevance of this blog post, you can understand why I found the paper “Glycosylation is anAndrogen-Regulated Process Essential for Prostate Cancer Cell Viability”* closely connected to my previous work. For postdoctoral researchers the world over, their research projects are like their own children. And so, there is always the urge to compare their own work with similar work done by others.
*(Glycosylation is anAndrogen-Regulated Process Essential for Prostate Cancer Cell Viability
Munkley, Jennifer et al.
EBioMedicine , Volume 8 , 103 – 116)
To begin with, prostate cancer ranks second in the United States for the high rate of mortality seen in men. And the number one culprit responsible for prostate cancer is the androgen hormone. You would clearly believe that dealing with the androgen hormone would take care of the cancer. Well, yes and no!
Yes, the first form of treatment following a PSA test (it measures the levels of PSA, which indicates the levels of the androgen hormone) would determine if the patient requires androgen deprivation therapy. And yet, while the cancer goes into remission following this treatment, in some individuals, the tumor relapses. Such tumors have been named castration resistant prostate cancer (CRPCa). The CRPCa tumors are menacing and far more aggressive than the initial hormone-dependent tumors.
Against this backdrop of information, the results of the EBioMedicine paper are quite interesting, to say the least. The study was a collaborative effort of multiple institutions across the UK andNorway. The main research was conducted in Newcastle University and their press release states that the results could prove to be a revolutionary advance in the diagnosis and subsequent management of prostate cancer.
Getting down to the meat of the study, we notice that this particular research went beyond laboratory-raised cells and included patient data. The authors mention this as their unique contribution to the research study. The data involved 3 replicates of the prostate cancer cellline LNCaP treated with androgen and 3 replicates of LNCaP that were grown inthe absence of the hormone. The RNA from these cells was sequenced for information and comparison. Similarly, RNA from 7 patients were analyzed prior to and post androgen-deprivation therapy.
The genes that were upregulated and downregulated could be compared between LNCaP and the patients. The RNA was treated with RNASeq (RNA sequencing) analysis to obtain the data. In LNCaP, the expression of 2760 genes was downregulated and that of 3339 genes was upregulated in the presence of androgens. Now, the authors compared the upregulated genes in the LNCap cell with the downregulated genes in the patient samples that were deprived of androgen. A similar comparison was carried out with the downregulated genes in the LNCaP cell with the upregulated genes in the patient samples deprived of androgen.
Both the comparisons were able to bring forth nearly 700 genes that were found to be regulated in a reciprocal fashion in response to the presence or absence of androgens. The 700 genes were then classified based on the relevant signaling pathways. The genes were found to belong to the endoplasmic reticulum stress pathway, the fatty acid metabolic pathway, and the lipid biosynthetic pathway, among others. However, the authors noted that they were the first to observe a pathway that had not been mentioned earlier in the prostate cancer field. This new pathway was the glycosylation pathway and it was regulated by androgen.
Digging deeper into the data they found the expression of 8 glycosylation genes was increased in the presence of androgens.These genes all encode enzymes that are regulated by the androgen receptor. Infact, 6 of these genes have been newly identified in this study. These genes are regulated early by the androgen receptor and are upregulated in prostate cancer.
In fact, when the expression of 2 of these enzymes (GCNT1 and GALNT7) was inhibited with siRNA, the prostate cancer cells found their ability to survive was hampered. The data showed the androgen receptor played an important role in regulating glycosylation-associated genes.
Glycosylated proteins play roles in cell signaling, cellular adhesion, surveying the immune system, communicating with the cell matrix, and metabolic functions of cells. With such a diverse role and impact on the functioning of the cells and the organism as a whole, the discovery that the glycosylation pathway and specific glycosylated enzymes are regulated by the androgen receptor is a significant one.
The 8 significant genes that were discovered in this study play roles in 4 glycosylation pathways. These 4 pathways have been shown to be important in the cancer process. Changes in the 8 enzymes cause changes in the structure and function of glycans. These glycans, in turn, have a significant effect on metastases, the extracellular matrix environment,and the cell surface. In fact, glycans may now be the new set of biomarkers to detect on different proteins in cancer.
To put things together, this research study has shed light on the mechanistic workings of glycan proteins by detecting the role of the associated enzymes on the function of the glycan proteins. The role of the androgen receptor in 4 glycosylation pathways that influence metastases and cancer progression is also significant in prostate cancer.
The new potential biomarkers in the glycosylation enzymes provide yet another target for therapeutic interventions in prostate cancer. In the current world of personalized medicine, identifying these markers will aid in specific drug targeting.