Researchers uncover why typically normal protein drives prostate cancer

A protein whose function is normally to define the prostate's development tells cells to continue growing in cancer. 

Study: NSD2 is a requisite subunit of the AR/FOXA1 neo-enhanceosome in promoting prostate tumorigenesis. Image Credit: Kateryna Kon/Shutterstock.com
Study: NSD2 is a requisite subunit of the AR/FOXA1 neo-enhanceosome in promoting prostate tumorigenesis. Image Credit: Kateryna Kon/Shutterstock.com

In a recent study published in Nature Genetics, researchers investigated the involvement of the androgen receptor (AR) in prostate cancer (PCa) growth and progression.

Background

AR is principally responsible for prostate cancer, which is the most frequent cancer among males in North America. AR regulates prostate development in normal cells but promotes tumor growth in PCa. AR activity is changed in prostate cancer, resulting in a dependence on AR for tumor development and survival, especially in metastatic castration-resistant PCa (mCRPC). AR is the primary focus of therapy following surgery or radiation. Investigating androgen receptor chromatin dynamics and cofactors could inform novel drug development efforts.

About the study

The present study investigated the molecular processes behind AR activity and its implications for therapeutic methods in mCRPC.

The researchers used Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-associated protein 9 (Cas9) to make an endogenous AR reporter system. CRISPR screening uncovered cofactors implicated in androgen receptors and prostate cancer. They sourced the enhanceosome, a complex of several proteins, including transcription and other epigenetic factors, that assemble on deoxyribonucleic acid (DNA) at precise places to stimulate gene expression. They contrasted these to the neo-enhanceosome.

The researchers explored various approaches to reduce or eliminate nuclear receptor-binding SET domain protein 2 (NSD-2) expression in prostate cancer cells. They used gene knockout to transduce cells using single-guide ribonucleic acids (sgRNA) targeting NSD-1 and NSD-2. They altered the KLK3 gene in AR-driven lymph node carcinoma of the prostate (LNCaP) cells to insert the mCherry coding sequence, which was then fused in-frame to the kallikrein-related peptidase 3 (KLK3) gene using an endopeptidase sequence.

They transfected cells with gene-targeting ON-TARGETplus SMARTpool siRNAs (or ASOs) followed by EPZ-6438 treatment for 72 hours. They investigated whether EPZ-6438, a selective inhibitor of the histone methyltransferase EZH2, could inhibit tumor growth.

Researchers phenotypically evaluated NSD2-deficient PCa cells and produced LLC0150, a chemical that inhibits NSD-1 and NSD-2. Total RNA and protein levels revealed that target genes were knocked down efficiently (above 80%). The Bliss approach determined the synergy between pharmacological treatments. The CRISPR screen identified AR binding to chromatin and chimeric AR half-motifs.

The researchers used NOD SCID mice and prostate cancer patient samples from Michigan University archives. They also used vertebral cancer of the prostate (VCaP), human embryonic kidney 293 (HEK293FT) cells, LNCaP, and 22RV1-enabled cell culture experiments. The researchers compared mycoplasma and cell line genotyping findings to short tandem repeat profiles from the American Type Culture Collection (ATCC) database.

They performed proliferation assays, Matrigel invasion assays, quantitative polymerase chain reaction (PCR), gene set enrichment analysis, and immunofluorescence. Assessments included chromatin immunoprecipitation sequencing (ChIP-seq) and HOMER motif identification.

Results

Researchers found that NSD-2 changes the action of AR, a crucial regulator of proper prostate growth. When AR attaches to NSD2, it promotes fast cell division and development, resulting in prostate cancer. NSD-2 is a critical component of AR enhanceosome complexes in prostate cancer cells, suggesting that NSD-2 is a therapeutic target for mCRPC. The AR acts as a transcription factor, activating genes that drive the differentiation of luminal epithelial cells.

NSD-2 is an AR coactivator overexpressed in altered prostate luminal epithelial cells. The AR complex's transcriptional activity is dependent on its methyltransferase function. NSD-2 inactivation affects AR binding in more than 65.0% of its tumor cistrome, reducing characteristic cancer traits. NSD-2-dependent AR locations contain the chimeric forkhead box protein A1 (FOXA1): androgen receptor motif, which comprises tumor-specific androgen receptor enhancer circuits. NSD-2 functions as a histone methyltransferase, shielding chromatin from repressive marks and promoting gene expression.

NSD-2 knockdown inhibits cancer development but does not eradicate it. NSD-1 and NSD-2 enable oncogenic AR activity separately, with NSD-2 acting as a molecular switch to activate characteristic cancer features. Loss of NSD-2 enhances dependence on NSD-1 in AR-addicted PCa cells, making NSD1/2 paralogs targetable co-vulnerabilities. LLC0150, which degrades NSD-1 and NSD-2, demonstrated selective efficacy in androgen receptor-dependent and NSD-2-altered cancer cells.

Compounds degrading NSD-1 and NSD-2 eliminated prostate cancer cell lines. The degraders targeted cancer cells only, causing no harm to normal cells. However, further research is required to improve the degrader since the initial version was not transferable to a mouse model. The data indicate that NSD-1- or NSD-2-targeting drugs might be used with AR antagonists to achieve synergistic benefits in prostate cancer therapy.

Conclusion

Based on the study findings, prostate cancer cells depend on androgen receptors for progression, with AR activity significantly reprogrammed in malignant stages. The production of neo-enhancers and the expansion of the androgen receptor enhancer circuitry are necessary to establish and maintain aggressive PCa phenotypes.

The finding of NSD-2 as a component of AR enhanceosome complexes implies novel paths for therapeutic targeting in mCRPC. The findings emphasize the necessity of knowing AR's involvement and related cofactors in developing effective PCa therapies.

Journal reference:
Pooja Toshniwal Paharia

Written by

Pooja Toshniwal Paharia

Pooja Toshniwal Paharia is an oral and maxillofacial physician and radiologist based in Pune, India. Her academic background is in Oral Medicine and Radiology. She has extensive experience in research and evidence-based clinical-radiological diagnosis and management of oral lesions and conditions and associated maxillofacial disorders.

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