Chromatin Openness Illuminates Prostate Cancer Plasticity

A recent study from the University of Eastern Finland's Institute of Biomedicine, published in Nucleic Acids Research, points to the SIX2 protein as a potential factor contributing to the increased plasticity and treatment resistance observed in prostate cancer cells. This finding could have significant implications for addressing one of the major challenges in prostate cancer treatment: the ability of cancer cells to develop resistance to therapy.

Prostate cancer remains the most prevalent cancer among men and is the second leading cause of cancer-related deaths in Western countries. The growth of prostate cancer is driven by androgens, and treatments often involve androgen receptor inhibition therapies, particularly for aggressive or advanced stages of the disease. Nonetheless, some cancer cells manage to resist these treatments, leading to a condition known as castration-resistant prostate cancer.

A key factor in this resistance is the plasticity of cancer cells, which allows them to alter their level of differentiation and revert to a stem cell-like state. This adaptability helps cancer cells evade the effects of hormonal therapies. However, the precise mechanisms that contribute to this plasticity and subsequent treatment resistance have not been fully elucidated.

"Identifying the factors that contribute to treatment resistance in prostate cancer and understanding how cancer cells change their degree of differentiation is crucial. This knowledge could lead to new therapeutic targets and potentially even a cure for these lethal cancer types," states Kirsi Ketola, an Academy Research Fellow and Adjunct Professor at the University of Eastern Finland.

Ketola's research lab investigated factors that might affect treatment resistance in prostate cancer. They focused on the role of chromatin, the material that packages DNA in cells. Chromatin is less tightly packed in regions where genes are actively expressed, making these areas more accessible. The Ketola Lab treated androgen-dependent prostate cancer cells with enzalutamide, an androgen receptor inhibitor, and observed changes in chromatin openness.

The study revealed that enzalutamide treatment led to a greater number of newly opened chromatin sites compared to new closed ones. These open sites were predominantly located in regions of DNA with binding sites for the SIX2 protein. This suggests that the increased activity of SIX2 could be responsible for the heightened plasticity of cancer cells following drug treatment.

In essence, inhibiting the androgen receptor appears to modify the gene regulation within cells, enabling the expression of genes that are usually silent and altering the cellular state.

The SIX2 protein plays a crucial role during embryogenesis by keeping cells in an undifferentiated state, thereby maintaining their potential to differentiate. The study found that SIX2 could regulate the differentiation degree of prostate cancer cells, even those without androgen receptors. Notably, the activity of the SIX2 gene rose in cancer cells after enzalutamide exposure, particularly in cells lacking androgen receptors.

Doctoral Researcher Noora Leppänen highlighted that silencing the SIX2 gene significantly reduced the malignancy of hormone therapy-resistant cancer cells. This was evidenced by a decrease in the stem cell-like properties of the cancer cells, such as their ability to migrate, invade, and metastasize. Experiments in zebrafish also showed reduced cell division and cancer spread following SIX2 silencing.

These findings suggest that targeting the SIX2 protein could be a promising strategy for developing treatments aimed at combating metastatic and hormone therapy-resistant prostate cancers.