Researchers at the University of Michigan Rogel Cancer Center have identified a gene that plays a key role in prostate cancer cells that have transitioned to a more aggressive and treatment-resistant form. The gene may be indirectly targeted by an existing class of drugs, suggesting a potential therapeutic strategy for patients with aggressive prostate cancer subtypes. This work advances previous studies that found that prostate cancer cells undergo a process called lineage plasticity, in which they become resistant to the androgen receptor (AR-α), a key target in prostate cancer.
This transition from androgen receptor dependence is a continuum in which cancer cells assume alternative identities to those typical of most prostate cancers that are dependent on the androgen receptor. In this new study, scientists examined what factors might be causing this transition. They identified the gene PROX1 (Prospero homeobox 1), which plays a role in determining cellular identity in both normal and cancer cells. The team discovered that as prostate cancer cells transition to an alternate identity, PROX1 becomes more highly expressed.
Their studies implicating PROX1 began by examining tumor biopsies from patients who had undergone lineage plasticity. PROX1 was the most upregulated gene. By examining hundreds of tumors from patients along the lineage plasticity continuum, they confirmed PROX1 as an early marker of lineage plasticity. Indeed, they found that tumors with low AR-a activity (called double-negative prostate cancer), as well as tumors that completely lose expression (called neuroendocrine prostate cancer), activated PROX1. In further experiments, the team demonstrated that PROX1 expression was inversely correlated with AR-α expression in tumor datasets from patients with prostate cancer.
Adding PROX1 to prostate cancer cells also deactivated AR-α. Therefore, it is likely that PROX1 regulates this receptor: this could explain why the androgen receptor is deactivated when tumors undergo lineage plasticity and abandon the typical identity of glandular prostate cancer. Numerous studies have clarified the fundamental role of PROX1 in regulating cell stemness, metabolic plasticity, chemoresistance, and distant metastasis in various tumors. As an important regulator of the WNT signaling pathway, this positions PROX1 as a key regulator of the metastasis process in aggressive tumors.
PROX1 significantly increased the mRNA levels of stem cell genes (CD44, CD133, ONECUT2, and IGF2BP1), epithelial-mesenchymal transition genes (such as E-cadherin, N-cadherin and Snail), and invasion-related genes (MMP2). Previous studies have shown that inhibition of the AR signaling pathway can upregulate neuroendocrine plasticity factors, including SPINK1 and TRIM59, and that androgen-treated CaP cells exhibited reduced PROX1 levels, similar to AR-α inhibitors. AR inhibition in LNCaP cells increased the expression of PROX1 and neuroendocrine markers.
Conversely, overexpression of AR-α in NCI-H660 cells reduced its expression. In other studies, enzalutamide increased the expression of neuroendocrine markers, which was then compromised following PROX1 inhibition. Subsequently, the team eliminated PROX1 expression using genetic methods in both double-negative prostate cancer and neuroendocrine prostate cancer cells. The cells then stopped growing and began dying, suggesting that targeting PROX1 could be an effective way to control these tumors. One challenge is that PROX1 is a transcription factor, and this type of protein is difficult to target with drugs.
Seeking an alternative solution, the team turned to the cellular network of PROX1. Examining the proteins that bind to PROX1, histone deacetylases (HDACs) were among the key partners, leading the scientists to hypothesize that HDACs might cooperate with PROX1. Since PROX1 is not pharmacologically applicable according to conventional knowledge, the scientists believe that targeting HDACs could be similar to targeting PROX1. It’s already known that HDACs play a role in cancer, and several HDAC inhibitors have been approved for cancers other than prostate cancer.
The team discovered that prostate cancer cells expressing PROX1 were highly sensitive to histone deacetylase inhibitors, and that treatment with these drugs reduced the PROX1 protein. As PROX1 expression decreased, the tumor cells died—the impact was similar to what occurred when the team genetically removed PROX1 from the cells. Therefore, histone deacetylase inhibitors could be repurposed to treat resistant forms of prostate cancer.
- Editesd by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
Duan Z et al. J Clin Invest. 2025; 135(11):e187490.
Liu C, Chen J et al. Cancer Lett. 2024; 597:217068.
Sakurai K et al. Hum Cell. 2024; 37(5):1559-1566.
