Researchers at the École Polytechnique Fédérale de Lausanne (EPFL) and Johns Hopkins University have identified a significant enzyme, KMT2D, that plays a crucial role in the development and treatment of prostate cancer. The findings, led by Wouter Karthaus at EPFL and Eneda Toska at Johns Hopkins, highlight KMT2D as a key epigenetic regulator affecting how prostate tumors grow and respond to therapies.
Prostate cancer often depends on the androgen receptor to fuel its growth. Standard treatment typically involves hormone-based therapies aimed at blocking this receptor’s signaling. Over time, however, many prostate cancers adapt, resulting in what is known as castration-resistant prostate cancer (CRPC). While some CRPCs continue to rely on androgen receptors, others shift away from this dependency, complicating treatment options.
The research team discovered that KMT2D facilitates the androgen receptor’s ability to access and activate essential genes related to tumor growth. It does so by modifying chromatin structure, the complex of DNA and proteins within cells, allowing the androgen receptor and associated proteins to reach their target sites more efficiently. This mechanism supports the ongoing activity of androgen receptor-driven prostate cancers, which rely on this pathway to proliferate.
Furthermore, KMT2D is vital in a particularly aggressive subtype of CRPC known as the “stem cell-like” subtype. In these instances, KMT2D helps maintain a hybrid cellular identity by regulating different transcription factors, particularly those in the AP-1 family such as FOSL1, which are associated with stem-like characteristics and resistance to therapy.
The researchers employed a variety of techniques, including genetically engineered prostate cancer cell lines, patient-derived organoids, single-cell sequencing, and animal models, to arrive at these conclusions. Silencing or removing KMT2D disrupted cancer cells’ capacity to uphold their identities, rendering them more susceptible to treatment. In preclinical models, inhibiting KMT2D significantly enhanced the effectiveness of certain anti-cancer drugs, including PI3K/AKT inhibitors and adenosine receptor inhibitors.
These findings suggest that targeting KMT2D could provide a new therapeutic avenue for prostate cancer treatment. Disabling this enzyme may resensitize tumors to existing therapies or slow their progression into more aggressive forms. The research emphasizes the necessity of tailoring treatments to specific tumor subtypes and using epigenetic profiling to guide therapy decisions.
Wouter Karthaus remarked, “With the ongoing surge in prostate cancer cases and the resulting increase of patients developing drug-resistant disease, it is important to understand how prostate cancer becomes drug resistant and discover new treatment avenues. KMT2D represents such a new avenue.”
The study also involved contributions from several respected institutions, including Memorial Sloan Kettering Cancer Center, KU Leuven, and AstraZeneca, among others. As the understanding of prostate cancer’s complexities deepens, ongoing research into enzymes like KMT2D could lead to more effective treatments and improved outcomes for patients.
