NSD1/2 may serve as potential therapeutic targets in prostate cancer

Investigators have discovered that the protein NSD2 may alter the activity of the androgen receptor (AR) and aid transcription factors such as FOXA1, HOXB13, and ETS in redistributing AR on the chromatin, thus promoting prostate tumorigenesis.¹

With the loss of NSD2, AR-addicted prostate cancer cells upregulated NSD1.

The findings were published in Nature Genetics.

According to the authors, these data suggest that NSD1 and NSD2 may be viable co-targets in the treatment of patients with advanced prostate cancer.

“Our study is one of the first molecular explanations for this functional duality of the androgen receptor,” said lead author Abhijit Parolia, PhD, Rogel fellow and assistant professor of pathology at University of Michigan Rogel Cancer Center, Ann Arbor, in a news release on the findings.² “NSD2 is a cancer specific collaborator of the androgen receptor that essentially rewires its activity to support prostate cancer development.”

Both FOXA1 and HOXB13 have been previously implicated in driving the AR’s reprogramming upon transformation on the chromatin. Since both transcription factors are also found in normal epithelial cells, the investigators sought to understand if there are additional co-factors that may contribute to this process. For the study, they analyzed the enhanceosome, a complex of multiple proteins, vis CRISPR screening.

They first found that NSD2 is expressed in prostate cancer cells, but not normal prostate cells. When NSD2 is present, it enables functional binding of AR at chimeric half-motifs, majorly compromising the AR neo-enhancer circuitries. When the team inhibited NSD2 expression in prostate cancer cells, AR binding was disrupted without an effect on AR protein levels and hallmark cancer phenotypes were abolished. However, NSD2-deficient prostate cancer cells remained viable despite a loss of neoplastic features.

According to the authors, this suggested that NSD2 paralogs may sustain AR activity through alternative mechanisms. To evaluate this, they tested the impact of NSD1 and NSD3 loss individually. They discovered that unlike NSD3 loss, NSD1 loss led to significant attenuation of the AR and MYC gene programs, diminished hyperproliferative pathways, and had the strongest reduction in H3K36me2 levels upon a single gene loss.This suggests that the related protein, NSD1, may work alongside NSD2 in promoting prostate tumorigenesis.

The findings also showed that with the loss of NSD2, AR-addicted prostate cancer cells upregulated NSD1, suggesting that residual oncogenic AR activity may be sustained in these cells. The co-inactivation of both proteins with a dual PROTAC degrader, called LLC0150, resulted in preferential acute cytotoxicity in AR-positive prostate cancer.

Based on these findings, the authors posit that further development of NSD-targeting therapeutics and an evaluation of their safety and efficacy in preclinical and clinical studies is warranted.

“By degrading NSD1 and NSD2, we can more directly target cancer and avoid the normal tissue,” explained 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, in the news release.² “Our study suggests if we’re able to develop NSD1/2-targeting agents, they could potentially be combined with FDA-approved androgen receptor antagonists and have a synergist effect in terms of treatment.”

References

1. Parolia A, Eyunni S, Verma BK, et al. NSD2 is a requisite subunit of the AR/FOXA1 neo-enhanceosome in promoting prostate tumorigenesis. Nat Genet. 2024. doi:10.1038/s41588-024-01893-6

2. Researchers identify factor that drives prostate cancer-causing genes. News release. Michigan Medicine – University of Michigan. September 5, 2024. Accessed September 11, 2024. https://www.newswise.com/articles/researchers-identify-factor-that-drives-prostate-cancer-causing-genes