Cancer scientists at the Rogel Center here identify a key mechanism by which the normally normal protein goes awry and fuels cancer. During this process, when the androgen receptor binds to NSD2, it then results in rapid cell division and growth which leads and promotes the development of prostate cancer. Thus, this work reveals a previously unknown phenomenon: while the normal function of the androgen receptor is to define the development of the prostate, to indicate to the cells to stop growing and to maintain a normal prostate, in cancer , and under the influence of NSD2, it does the opposite: it tells cells to grow and promote the development of cancer.
How does it “work”? When the NSD2 protein, by binding to the androgen receptor, alters its normal function, this triggers an acceleration of the division and growth of cancer cells.
The study is one of the first to offer “ a molecular explanation of this functional duality of the androgen receptor “, summarizes one of the lead authors, Dr. Abhijit Parolia, professor of pathology at Michigan Medicine. “NSD2 is a specific collaborator of the androgen receptor in cancer, which reprograms the activity of the receptor in a way that supports the development of prostate cancer.”
The researchers began with a CRISPR screen to look for cofactors involved in the androgen receptor and prostate cancer. They sifted
“the enhanceosome”, a complex of several proteins, including transcription factors and other epigenetic factors,
which assemble on DNA at specific locations to stimulate gene expression. Carcinogenic transcription factors infiltrate it, reorganizing its careful assembly in ways that stimulate the expression of carcinogenic patterns. This work reveals that:
- NSD2 is expressed in prostate cancer cells, but not in normal prostate cells;
- NSD2 is involved in metastatic prostate cancer;
- its role proves fundamental at the earliest stage of cancer development.
- when NSD2 is present, NSD2 rearranges the location of the androgen receptor on DNA, placing it next to sites occupied by known carcinogenic genes and factors.
- This constitutes “a whole machinery” – with other susceptibility genes such as ERG and FOXA1 – which will regulate oncogene expression.
What implications? Researchers will now attempt to indirectly target oncogenic genes by targeting NSD2 or other epigenetic components.
Thus, this work also shows that:
- when NSD2 expression is reduced or stopped in prostate cancer cells, this returns the cells to a more normal state and slows the growth and spread of cancer cells; However, this does not eliminate cancer;
- a related protein called NSD1 works “team” with NSD2 could also be a possible therapeutic target.
- thus, a compound that degrades both NSD1 and NSD2 can destroy prostate cancer cell lines.
“By degrading NSD1 and NSD2, we can target cancer more directly and avoid damage to normal tissues. Our work suggests that agents targeting NSD1/2, combined with FDA-approved androgen receptor antagonists, would provide an effective synergistic effect against the tumor.”
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