June 20, 2012

Unusual Mechanism Generates Prostate Cancer Gene Product

(Ivanhoe Newswire) — A new study opens doors to understanding prostate cancer with the identification of a potential new pathway in prostate cancer cells by which cancer-driving gene products can be created.

"Our work shows that cancers have many more tricks than we thought to generate potential cancer-driving genes or gene products," Hui Li, Ph.D., assistant professor of pathology at the University of Virginia in Charlottesville, and a recipient of an Innovative Research Grant from Stand Up To Cancer (SU2C), was quoted as saying. The AACR is the scientific partner of SU2C.

Gene fusion is a common characteristic of human cancers. Frequently, the protein products of these gene fusions (which are generated via an RNA intermediate) have a key role in cancer creation. For example, the protein that drives chronic myeloid leukemia, BCR-ABL, is generated via RNA intermediates from a fusion gene formed by chromosomal translocation – an event that involves the exchange of genomic DNA between two individual chromosomes.

"For many years, chromosomal translocation was considered the sole way in which single RNAs consisting of copies of parts of two genes, so-called fusion RNAs, could be generated," Li was quoted as saying. "We have shown that fusion RNAs can be generated without changes to DNA by a new mechanism that we are calling cis-SAGe [cis-splicing of adjacent genes]."

A fusion RNA formed from parts of the SLC45A3 and ELK4 genes was recently identified in prostate cancer cells in the absence of any DNA alterations. It was confirmed in two prostate cancer cells lines that the SLC45A3-ELK4 fusion RNA could be detected, even though it was not evident that genomic DNA rearrangement occurred.

When they conducted a detailed molecular analysis of the prostate cancer cell lines, they found indication that the SLC45A3-ELK4 fusion RNA was generated by cis-SAGe. SLC45A3 and ELK4 are neighboring genes, and cis-SAGe occurred when an RNA that crossed the boundary between the two genes was formed.

The protein CCCTC-binding factor normally functions to protect SLC45A3 and ELK4 from each other. It was found that its protein levels at the gene boundary were inversely correlated with the amount of SLC45A3-ELK4 fusion RNA generated, which gives molecular insight into how the quantity of this fusion RNA could be regulated.

Two observations suggest that the SLC45A3-ELK4 fusion RNA in prostate cancer plays a functional role. First, it promoted the growth of the two prostate cancer cell lines in culture. Second, its levels in human prostate samples correlated with prostate cancer disease progression – normal prostate tissue had the lowest levels and prostate cancer specimens from men with metastatic disease had the highest levels.

"These data are not sufficient to say that the SLC45A3-ELK4 fusion RNA has a causal role in prostate cancer," Li was quoted as saying. "But they are highly suggestive, and I am very excited that this high-risk project, which I would not have been able to pursue without the grant from Stand Up To Cancer, has uncovered what seems to be a new way in which cancer can be driven."

Source: Cancer Discovery, June 2012