Molecular switches turn on unwanted evolution of prostate tumors

Giuseppina Carbone of the Institute of Oncology in Bellinzona (IOR, USI), MD-supervised researchers at the Institute for Prostate Cancer Biology, have unexpected mechanisms to drive ERG fusion, the largest group in the evolution of prostate tumors. I found. -Positive prostate cancer.The study is published at Nature Communications..

prostate cancer Is one of the most common causes of malignancy and death in men worldwide. About 50% of prostate Tumors (ERG fusion-positive prostate cancer) have a fusion between the ERG gene and the promoter region of the TMPRSS2 gene. This chromosomal rearrangement causes abnormal production of ERG and promotes tumor progression. However, the mechanism by which ERG contributes to tumorigenesis and promotes progression from primary to metastatic and hormone-resistant prostate cancer remains unclear.

Researchers have identified EZH2 in search of proteins that may interact and cooperate with ERG. Dr. Carbon explains: “I found that EZH2 binds and adds. Methyl group For ERG that functions as a coactivator. EZH2 is ERG’s criminal partner in the progression of prostate cancer. ”

Researchers have observed that the addition of a methyl group to a specific site in ERG enhances its tumorigenic activity. “Methylation of lysine 362 is like a switch that changes ERG from a quiescent state to a very active state. This modification occurs at a critical position on the boundary of the internal self-suppressing domain of the ERG protein.” Dr. Cavalli said.

By methylating lysine 362, ERG alters its conformation, enhances its activity and promotes the expression of multiple genes involved in tumor progression and metastasis. Using a preclinical model of ERG fusion-positive prostate cancer, researchers elucidated the role of the gene PTEN, another important player in the activation of EZH2-ERG. PTEN deletions are widespread in prostate cancer and are often associated with ERG fusion-positive tumors. Dr. Carbone’s group observed that loss of PTEN increased EZH2 activity and thus increased ERG methylation. This explains the combined effects of these events in the patient.

“Our findings define a new therapeutically viable pathway for treating patients positive for ERG fusion. Prostate cancer “In various experimental models, drugs that inhibit EZH2 and prevent ERG methylation reverse and block ERG-induced molecular and phenotypic changes,” said Katapano. tumor growth. This strategy can be very effective in more aggressive ERG fusion-positive prostate tumors. Interestingly, other tumors expressing ERG may utilize a similar mechanism of EZH2-mediated activation. These aspects are currently under investigation. ”

Provided by Università della Svizzeraitaliana