New progress in prostate cancer research: androgen receptor co-activator BAP18
BAP18 coactivates androgen receptor action and promotes prostate cancer progression
Research Background
Studies have found that 18 kDa BPTF related protein (BAP18) is mll1 - wdr5 complex components BAP18, however, is an unknown protein, BAP18 biological functions and the detailed mechanism is not clear.
Androgen receptor is a member of the transcription factor ,it play an important role in prostate cancer (PCA) and castration resistant prostate cancer (CRPC) .
Materials and methods
Fruit flies, synthesis of androgen (DHT) before and after treatment of 22Rv1 cells,HEK293 cell immunoprecipitation (co-ip); RNA - seq, qPCR etc.
Results
In fruit flies, CG33695 is the co-activator of androgen receptor
Many studies have shown that AR auxiliary adjusting factor in AR mediated transcription play an important biological function using relevant PEV araf - 1 (araf - 1 - PEV model) in the experimental system of fruit flies, we have several kinds of known protein was isolated, the function of these proteins is a common regulators as androgen receptors, through the different molecular mechanisms involved in androgen receptor regulation process in this study, we have to separate and identify an unknown function protein, cg33695 mediated transcription activity involved in regulating fruit flies araf - 1 GFP report gene expression system, cg33695 loss function of two mutant (cg33695k07716, cg33695dg06604) respectively make araf - 1 mediated transcription activity decline, this suggests that in the fruit fly cg33695 associated with androgen receptors in order to confirm the results, the human homologous cg33695 flies genetically modified (gm), we observed cg33695 or c17orf49 in eye plate reinforced GFP araf - 1 mediated transcription, four species BAP18 has high homology, contains a conservative SANT domain, this structure domain associated with chromatin proteins or transcription factors.
BAP18 And androgens interact with each other
To study human homologous cg33695 (BAP18) AR induction of transcription and the effect of using immune co-precipitation (Co - IP) experiment testing BAP18 and AR the interaction of AR and FLAG marker BAP18 expression plasmid transfection HEK293 cells, the research results show that when there are AR ligand (DHT) in the interaction between AR and BAP18 stronger.
The results of immunofluorescence showed that, regardless of whether or not the AR ligand was processed,BAP18 was located in the nuclear zone, and the nucleus was distributed in DHT with the AR.
BAP18 egulate AR mediated transcription in mammalian cells
In order to systematic study BAP18 within the scope of whole epigenome affect AR mediated gene regulation, application of high-throughput sequencing technologies to knockout mRNA expression was analyzed in the experiment From the transcriptome data, we in the synthesis of testosterone (DHT) treated 22 rv1 cells were found in 609 differentially expressed genes (DEGS), the gene regulation of the gene encoding BAP18 by siRNA some silence BAP18 significantly affect the gene expression induced by processing by DHT, suggests BAP18 genes involved in regulating AR mediated transcription In order to further test under the condition of existence and non-existence DHT BAP18 of multiple genes regulating function is similar, the comparative analysis of carrying shBAP18 22 rv1 cells before and after processing the transcriptome data in DHT, found that part of the target genes and androgen receptors in the study of gene regulation overlap in DHT shBAP18 cells before and after processing, the androgen induced gene expression change of 32 through KEGG pathway enrichment analysis to study the differentially expressed genes mainly involved in which cells process, the results showed that the main differentially expressed genes involved in cellular processes, human disease, the body static balance, etc
BAP18 raise the protein MLL1 associated with AR target gene promoter
The results showed that the interaction of BAP18 with MLL1 complex and androgen receptor plays a role in the regulation of AR mediated transcription.
BAP18 high expression of prostate cancer section
The expression of BAP18 in the sample of clinical prostate cancer is higher than benign prostatic hyperplasia (benign prostatic hyperplasia).
conclusion
This study found that BAP18 is flies experiment system and mammalian cells in androgen receptor activator, BAP18 participation MLL1 components and AR androgen response elements (ARE) AR target genes to raise, will adjust through the change of the group g protein modification AR dependent gene activation BAP18 prostate cancer cell proliferation and plays a key role in the progress of CRPC, whether BAP18 expression can be used as the prognosis of patients with prostate cancer CRPC and a potential target of treatment.
