NSD2 protein may be responsible for early development of prostate cancer

Researchers at the University of Michigan Rogel Cancer Center have discovered a key reason why a normally normal protein goes awry and fuels cancer.

They found that the NSD2 protein impairs the function of the androgen receptor, an important regulator of normal prostate development. When an androgen receptor binds to the NSD2 protein, it causes rapid cell division and growth, leading to prostate cancer. The study, published in Genetics of naturecould suggest a new way to therapeutically target prostate cancer.

These results shed light on a previously unknown phenomenon. The normal function of the androgen receptor is to control prostate development. It tells cells to stop growing and maintain a normal prostate. But in cancer, the androgen receptor does the opposite: it tells cells to keep growing and promotes cancer development.

“Our study is one of the first molecular explanations for this functional duality of the androgen receptor,” said study first author Abhijit Parolia, Ph.D., a Rogel Investigator and assistant professor of pathology at Michigan Medicine. “NSD2 is a specific collaborator of the androgen receptor in cancer that essentially reprograms its activity to support prostate cancer development.”

The researchers started with a CRISPR screen to look for cofactors involved in the androgen receptor and prostate cancer. They screened the enhanceosome, a complex of several proteins, including transcription factors and other epigenetic factors, that assemble on DNA at specific locations to boost gene expression. They compared this to something called the neo-enhanceosome. It’s a similar piece of machinery, but cancer-causing transcription factors sneak in, rearrange the fine assembly, and boost the expression of cancer-causing programs.

The androgen receptor is typically located along a specific line of sites in DNA. When the NSD2 gene is present, it rearranges the location of the androgen receptor “enhancerosome” on the DNA, placing it next to sites occupied by known cancer-causing genes and factors.

“This is the mechanism around genes that we know are involved in prostate cancer development, including androgen receptors, ERG and FOXA1. They all use this mechanism to regulate oncogenic expression. We are now working to indirectly target genes of interest by affecting these epigenetic components like NSD2,” said study co-senior author Arul M. Chinnaiyan, MD, PhD, director of the Michigan Center for Translational Pathology and the S.P. Hicks Professor of Pathology at Michigan Medicine.

Researchers have discovered that the NSD2 gene is expressed in prostate cancer cells, but not in normal prostate cells. The NSD2 gene was previously known to be involved in metastatic prostate cancer. This is the first study to show that it is fundamental in the earliest stage of prostate cancer development.

The team used several methods to reduce or stop the expression of NSD2 in prostate cancer cells and found that this returned the cells to a more normal state, slowing the growth and spread of cancer cells, but not eliminating the cancer. They discovered that a related protein called NSD1 works in concert with NSD2.

A compound that degrades both NSD1 and NSD2 successfully killed prostate cancer cell lines. The degrader specifically targeted cancer cells without affecting normal cells. Further work is needed to refine the degrader, as the initial version could not be translated to a mouse model.

“By degrading NSD1 and NSD2, we can more directly target cancer and avoid normal tissues,” Chinnaiyan said. “Our study suggests that if we can develop agents that target NSD1/2, they could potentially be combined with FDA-approved androgen receptor antagonists and have a synergistic effect in terms of treatment.”