An Androgen Receptor Network Plays Critical Role in Prostate Cancer

By Robert Dillard - Last Updated: September 30, 2022

A new study uncovered an androgen receptor (AR) network that may identify hotspots for therapy intervention in prostate cancer (PCa) patients. The findings were reported in the journal Molecular Metabolism.

The deviating activity of AR is known as one of the key drivers of castration-resistant PCa (CRPC). “Androgen signaling regulates gene transcription and lipid metabolism, facilitating tumor growth and therapy resistance in early and advanced PCa. Although direct AR signaling inhibitors exist, AR expression and function can also be epigenetically regulated. Specifically, lysine (K)-specific demethylases (KDMs), which are often overexpressed in PCa and CRPC phenotypes, regulate the AR transcriptional program,” the researchers wrote.

In this study, researchers used a multi-omics method to assess LSD1/UTX inhibition, two KDMs, in PCa and CRPC. They performed a mitochondrial stress test to analyze respiratory function following treatment with MC3324, a dual KDM-inhibitor. Subsequently, they conducted lipidomic, proteomic, and metabolic analyses.

The results showed that the inhibitor induced a global increase in H3K4me2 and H3K27me3 in concert with a significant growth arrest and apoptosis in androgen-responsive and -unresponsive PCa systems. The researchers observed that LSD1/UTX inhibition downregulated AR at both transcriptional and non-transcriptional level, demonstrating cancer selectivity, which they noted indicated its potential use in resistance to androgen deprivation therapy.

“Our data suggest a network in which epigenetics, hormone signaling, metabolite availability, lipid content, and mechano-metabolic process are closely related. This network may be able to identify additional hotspots for pharmacological intervention and underscores the key role of KDM-mediated epigenetic modulation in PCa and CRPC,” the researchers concluded.