A team led by Wouter Karthaus, head of the Laboratory of Resistance to Endocrine Therapies and Molecular Genetics at EPFL, and Eneda Toska of Johns Hopkins University has identified the KMT2D enzyme as a key regulator of prostate cancer. Their study reveals that it plays a central role in how prostate tumors develop, survive and respond to treatment, communicates EPFL.
Most prostate cancers rely on the androgen receptor to fuel their growth. These tumors are usually treated with hormone therapies that block androgen receptor signaling. However, over time, many prostate cancers adapt and become resistant, giving rise to “castration-resistant prostate cancers” (CRPC). Some CRPCs continue to rely on the androgen receptor, but others do not rely on it altogether, becoming more difficult to treat.
This is where KMT2D comes in. Scientists have discovered that this enzyme facilitates the androgen receptor’s access to key genes involved in tumor growth and their activation. It does this by changing the structure of chromatin, which is the dense protein coat of DNA in the cell.
Thus, the androgen receptor and its auxiliary proteins can access their target sites more efficiently. This helps maintain the activity of androgen receptor-dependent prostate cancers, which need this pathway to continue growing.
Treat or slow down the disease
The study, published in “Cancer Research,” also found that KMT2D plays a critical role in a particularly aggressive androgen receptor-independent form of CRPC called the “stem cell-like” subtype. Deletion or inhibition of KMT2D disrupted the ability of cancer cells to maintain their identity and made them more vulnerable to treatments. In preclinical models, therefore animal trials, blocking KMT2D amplified the effectiveness of certain anticancer drugs.
The results suggest that KMT2D could be an interesting therapeutic target in prostate cancer. Its deactivation could make tumors re-responsive to existing treatments or slow their progression towards more aggressive forms. The work also highlights the importance of tailoring treatments to specific tumor subtypes and using epigenetic profiling to guide therapeutic decisions.
According to Wouter Karthaus, “with the continued rise in prostate cancer cases and the resulting increase in the number of patients developing drug-resistant disease, it is important to understand how prostate cancer becomes drug-resistant and to discover new therapeutic avenues. KMT2D represents this new path.”
