Researchers at the University of Michigan Rogel Cancer Center identified a gene that plays a key role in prostate cancer cells that have transitioned to a more aggressive, treatment-resistant form. The gene can be indirectly targeted with an existing class of drugs, suggesting a potential treatment strategy for patients with aggressive subtypes of prostate cancer. The work advances earlier studies that found prostate cancer cells undergo a process called lineage plasticity, in which they become resistant to targeting the androgen receptor, a key target in prostate cancer. This transition away from dependence on the androgen receptor is a continuum with cancer cells taking on alternate identities from what is typical in most prostate cancers that rely on the androgen receptor. In this new study, scientists examined which factors might be causing this transition to occur.
They identified the gene PROX1 (Prospero homoebox 1), which plays a role in dictating cell identity in both normal cells and cancer cells. The team found that as prostate cancer cells transition to an alternate identity, PROX1 becomes more highly expressed. Their studies implicating PROX1 began by examining patient tumor biopsies that had undergone lineage plasticity. PROX1 was the top upregulated gene. By examining hundreds of patient tumors along the continuum of lineage plasticity, they confirmed PROX1 as an early marker of lineage plasticity. Indeed, they found that tumors with low activity of the androgen receptor (called double-negative prostate cancer) in addition to tumors that completely lose expression of the androgen receptor (called neuroendocrine prostate cancer) turn on PROX1.
In additional experiments, the team showed PROX1 expression was inversely correlated with androgen receptor expression in prostate cancer patient tumor datasets. Adding PROX1 to prostate cancer cells also turned off the androgen receptor. Therefore is likely that PROX1 is regulating the androgen receptor: it may be one explanation for why the androgen receptor gets turned off when tumors undergo lineage plasticity and transition away from the typical glandular prostate cancer identity. Numerous studies have elucidated the pivotal roles of PROX1 in regulating cell stemness, chemoresistance, metabolic plasticity, and distant metastasis in various cancers. As an important regulator in the WNT signaling pathway, this poses PROX1 as a main regulator of the metastasis process in aggresive cancers.
PROX1 significantly upregulated the mRNA levels of cell stemness genes (CD44, CD133, ONECUT2 and IGF2BP1), epithelial-mesenchymal transition genes (like E-cadherin, N-cadherin and Snail), and invasion-related genes (MMP2). Previous studies have demonstrated that inhibition of the AR signaling pathway can upregulate neuroendocrine plasticity drivers, including SPINK1 and TRIM59 and that PCa cells treated with dihydro-testosterone (DHT) exhibited a reduced level of PROX1, akin to AR inhibitory targets. AR knockdown in LNCaP cells increased the expression of PROX1 and neuroendocrine markers. Conversely, AR overexpression in NCI-H660 cells decreased their expression. In other investigations, enzalutamide enhanced and induced neuroendocrine marker expression was impaired following PROX1 knockdown.
Next, the team eliminated PROX1 expression with genetic methods in both double-negative prostate cancer and neuroendocrine prostate cancer cells. The cells then stopped growing and began to die, suggesting that targeting PROX1 could be an effective way to control these tumors. One challenge is that PROX1 is a transcription factor, meaning its function to turn on genes, and this type of protein is notoriously difficult to target with drugs. Looking for a workaround, the team turned to the company PROX1 keeps. By examining the proteins that bind to PROX1, among the top partners were histone deacetylases (HDACs), which let scientists hypothesized that HDACs might cooperate with PROX1. Since PROX1 is not druggable with the conventional knowldge, scientists deem that targeting HDACs might be like targeting PROX1.
HDACs are already known to play a role in cancer, and several HDAC inhibitors have been approved by the U.S. FDA for other cancers other than prostate. The team found that PROX1-expressing prostate cancer cells were very sensitive to HDAC inhibitors and treatment with these drugs depleted PROX1 protein. As PROX1 expression decreased, the tumor cells died: the impact was similar to when the team genetically removed PROX1 from the cells. Therefore histone deacetylase inhibitors coud be well repurposed to treat resistant forms of prostate cancers.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
Scientific references
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