Prostate cancer is one of the most common malignancies and causes of mortality in men worldwide. About 50% of prostate tumors (ERG fusion-positive prostate cancers) harbor a fusion between the ERG gene and the promoter region of TMPRSS2 gene. This chromosomal rearrangement leads to abnormal production of ERG and promotes tumor progression. However, the mechanism by which ERG contributes to the tumorigenesis and drives the progression from primary to metastatic and hormone-refractory prostate cancers is still unclear.
Researchers of the Prostate Cancer Biology group, directed by Giuseppina Carbone, M.D. (Institute of Oncology Research, IOR, affiliated to USI) discovered an unexpected mechanism that drives the evolution of ERG fusion-positive prostate cancers.
The study, made in collaboration with Prof. Carlo Catapano (Experimental therapeutic group, IOR), and Dr. Andrea Cavalli (Computational biology group, IRB), is published in the prestigious journal Nature Communications and is available here.
Looking for proteins that potentially interact and cooperate with ERG, researchers identified EZH2. Dr. Carbone explains: ” We discovered that EZH2 binds and adds a methyl group to ERG, acting as a co-activator. EZH2 is a partner-in-crime of ERG in prostate cancer progression”.
The researchers observed that the addition of a methyl group on a specific site of ERG was enhancing its tumorigenic activity.
“The methylation of lysine 362 is like a switch turning ERG from a quiescent to a very active state. This modification occurs in a critical position at the boundary of an internal auto-inhibitory domain in the ERG protein” explained Dr. Cavalli.
With the methylation on lysine 362, ERG changes its conformation and increases its activity, promoting the expression of multiple genes involved in tumor progression and metastasis.
Using preclinical models of ERG fusion-positive prostate cancer, the researchers unraveled the role of another important player in EZH2-ERG activation: the gene PTEN. Deletion of PTEN are widespread in prostate cancers and often associated with ERG fusion-positive tumors.
Dr. Carbone’s group observed that the loss of PTEN increased EZH2 activity and, therefore ERG methylation, thus explaining the combined effects of these events in patients.
“Our findings define a new therapeutically actionable pathway for treating patients with ERG fusion-positive prostate cancer and preventing further progression of the disease” said Prof. Carlo Catapano. In various experimental models, drugs that inhibit EZH2 and prevent ERG methylation reverse the molecular and phenotypic alterations induced by ERG and block tumor growth. This strategy could turn to be very effective in the more aggressive ERG fusion-positive prostate tumors. Interestingly, other tumors expressing ERG might exploit similar mechanisms of EZH2-mediated activation. These aspects are currently under investigation.
Zoma M, Curti L, Shinde D, Albino D, Mitra A, Sgrignani J, Mapelli SN, Sandrini G, Civenni G, Merulla J, Chiorino G, Kunderfranco P, Cacciatore A, Kokanovic A, Rinaldi A, Cavalli A, Catapano CV and Carbone GM. EZH2-induced lysine K362 methylation enhances TMPRSS2-ERG oncogenic activity in prostate cancer. Nature Communications (2021) 12, 4147. doi:10.1038/s41467-021-24380-6.
EZH2 induces methylation of ERG at lysine 362 (K362), leading to a conformational change that increases ERG activation. Loss of PTEN increases the ability of EZH2 to methylate ERG, further supporting ERG tumorigenic activity. ERG methylation causes extensive transcriptional reprogramming with activation of genes that increase intravascular spread and metastatic capacity, thus promoting prostate cancer progression.