Discovery of PROX1 Gene as an Early Indicator of Aggressive Prostate Cancer

Researchers at the University of Michigan Rogel Cancer Center have identified a crucial gene, PROX1, that significantly contributes to the progression of prostate cancer toward a more aggressive and treatment-resistant form. This gene plays a key role in the cellular transformation process known as lineage plasticity, which prostate cancer cells undergo to evade traditional therapies targeting the androgen receptor.

Prostate tumors that lose reliance on the androgen receptor — such as double-negative prostate cancer and neuroendocrine prostate cancer — display elevated levels of PROX1. The study found that increased PROX1 expression correlates inversely with androgen receptor activity and may actively regulate its suppression. Experimentally reducing PROX1 levels in aggressive prostate cancer cells led to halted growth and cell death, indicating its potential as a therapeutic target.

Given that PROX1 is a transcription factor—a type of protein traditionally difficult to target directly—researchers explored its associated molecular partners. They discovered that histone deacetylases (HDACs) interact with PROX1. Since HDAC inhibitors are already approved for other cancer treatments and can reduce PROX1 levels, this opens a promising avenue for therapy. When prostate cancer cells expressing PROX1 were treated with HDAC inhibitors, the drug depleted PROX1 and induced tumor cell death, mimicking the effects of genetic PROX1 suppression.

This research suggests that PROX1 is an early driver of prostate cancer's transition to a more aggressive and treatment-resistant state. Using HDAC inhibitors to target this pathway could offer a new treatment strategy for patients with limited options, especially those with advanced, androgen receptor-independent prostate cancers.

The findings were published in the Journal of Clinical Investigation, highlighting the importance of PROX1 in prostate cancer progression and providing insights into potential targeted therapies.