Prostate cancer biomarker

Prostate cancer is the most prevalent cancer and the second leading cause of cancer death in men. Serum prostate-speci?c antigen (PSA) screening is the gold standard biomarker for prostate cancer diagnosis and management. The problem is that the PSA test has poor speci?city. Epigenetic-based biomarkers may provide the next future step in prostate cancer diagnosis and prognosis, especially as genome-wide sequencing and analysis approaches. DNA methylation, posttranslational histone modi?cations, the incorporation of histone variants and expression of non-coding RNAs are four major epigenetic markers.

Low levels of cytosine methylation in non-CpG contexts have also been identi?ed by methylome sequencing in embryonic stem cells, oocytes and brain. 5mCpG promoter hypermethylation is the best-characterised epigenetic alteration in prostate cancer. The global levels of 5hmC have found to be strongly reduced in cancer, including prostate cancer.

Each miRNA can potentially bind and inhibit 200 or more different mRNAs simultaneously, and also each mRNA can be targeted by multiple miRNAs.

One of the main challenge there are limited bioinformatic tools and that our knowledge in the cancer epigenomic landscape needs a deeper understanding. New technologies, such as NGS for global epigenomic analyses and integration with genomic and transcriptomic data, will exponentially expand our understanding of prostate tumorigenesis and will yield more clinically informative epigenetic biomarkers to aid in disease strati?cation.

SMYD3 is a histone methyltransferase that plays a role in transcriptional regulation as a member of an RNA polymerase complex, which methylate histone H4 at lysine 5 (H4K5). In this study, we found Smyd3 deletion resulted in lower detection of pERK1/2 relative to control tumors without an overall change in total levels of Ras.

We used protein array technology to identify the MAP3K2 kinase as a target of SMYD3. The cytoplasmic kinase MAP3K2 is activated in response to a variety of stress and mitogenic stimuli, including epidermal growth factor (EGF), and relays signals to downstream MAP kinase components such as ERK1/2. EGF treatment triggered ERK1/2 phosphorylation, and this response was greatly reduced by SMYD3 depletion.

Because the intrinsic kinase activity of Map3K2 is not directly altered by methylation, we postulated that this modification event was involved in modulating a key protein–protein interaction. We find that amino acids 249–273 of MAP3K2 are sufficient for binding directly to the PP2A complex, via PPP2R2A, and methylation at K260 inhibits this interaction. Finally, the PP2Aphosphatase complex, a key negative regulator of the MAP kinase pathway, binds to MAP3K2 and this interaction is blocked by methylation.

A clinical implication of this work is the identification of SMYD3 as a candidate therapeutic target for pharmacologic intervention to treat pancreatic and lung cancers, as well as potentially other Ras-driven tumors.