Novel enzyme offers new look at male hormone regulation

UNC scientists' findings have implications for prostate cancer

CHAPEL HILL For the second time in less than a year, University of North Carolina at Chapel Hill scientists have purified a novel protein and have shown it can alter gene activity by reversing a molecular modification previously thought permanent.

The findings, published today (May 5) in the journal Cell, also show that the new protein plays a role in gene activation mediated by androgen receptor, a protein that responds to androgen hormones. In this regard, the novel protein may figure in the development of prostate cancer.

Androgens, particularly testosterone and dihydrotestosterone, determine male secondary sex characteristics and stimulate prostate cell growth. Lowering androgen levels usually can make prostate cancers shrink or grow more slowly.

In the study, the researchers said the new protein called JHDM2A, like the protein they reported on in the journal Nature in December 2005, is able to remove a methyl group from histone H3, one of four histone proteins bound to all genes.

"Human genes are so tightly compact within the nucleus that if the DNA of a single cell were unwound and stretched, it would be a line of about two meters in length. Histones are necessary to package the DNA so that it fits inside a cell's nucleus," said senior author Dr. Yi Zhang, professor of biochemistry and biophysics at UNC's School of Medicine and the university's first Howard Hughes Medical Institute investigator.

Zhang also is a member of the UNC Lineberger Comprehensive Cancer Center.

Because histones are so intimately associated with DNA, even slight chemical alterations of these proteins can have profound effects on nearby genes. Depending on their precise location and how many methyl groups are added, the presence of alterations can either turn on or turn off a gene.

In the study, Zhang learned that the JHDM2A specifically removes methyl-groups from lysine 9 of histone H3.

"The important thing is that H3K9 demethylation has been linked to transcription silencing, turning genes off. So that led us to pay attention to this protein's role in reversing whatever function K9 methylation might have," Zhang said.

In their experiments, the researchers learned that consistent with reversing a marker of gene silencing (H3K9 methylation), the protein functions as a co-activator in this case, a co-activator for the androgen receptor target genes.

Using human tissue cultures, including prostate cells, Zhang and his colleagues found that over-expression of JHDM2A greatly reduced H3K9 methylation level and led to upregulation, or switching on, of androgen receptor target genes. In contrast, when methylation was increased, the gene was silenced switched off.

It remains unclear for how many different human genes JHDM2A is a primary regulator. According to Zhang, the new findings indicate that the protein will provide another tool to enlist in studies of gene expression regulation.

"Given the androgen receptor link, we're now trying to identify the downstream target genes, as well as its role in prostate cancer," he said.

"Theoretically, this protein is a very important tool for gene expression studies. Practically, it provides a potential target for prostate cancer because of its enzymatic activity. And it is enzymatic activity that's the favorite target of drug development."

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Co-authors with Zhang are Drs. Keniche Yamane and Yu-ichi Tsoukada, postdoctoral scientists in Zhang's lab; Charalambos Toumazou and Jiemin Wong from Baylor College of Medicine; and Hediye Erdjument-Bromage and Paul Tempst from the Memorial Sloan-Kettering Cancer Center.

The research was funded by the National Institutes of Health.


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