Treatment resistance in prostate cancer, driven by the plasticity of cancer cells, presents a significant challenge. A study published in Nucleic Acids Research by researchers at the University of Eastern Finland Institute of Biomedicine identifies the SIX2 protein as a potential factor contributing to this resistance.
Prostate cancer, the most prevalent cancer in men and the second leading cause of cancer mortality in Western countries, is often treated with androgen receptor inhibition therapies. Despite initial effectiveness, cancer cells can develop resistance, leading to castration-resistant prostate cancer. The ability of cancer cells to revert to a stem cell-like state, known as plasticity, is suspected to underlie this resistance, though the contributing factors have remained elusive.
Investigating the Role of Chromatin in Treatment Resistance
The Ketola Lab at the University of Eastern Finland focused on uncovering new factors involved in treatment resistance. Their study examined chromatin openness in androgen-dependent prostate cancer cells treated with enzalutamide, an androgen receptor inhibitor. Chromatin, which packs DNA within cells, becomes looser in regions of active gene expression.
Following enzalutamide treatment, the researchers observed a significant increase in newly opened chromatin sites compared to newly closed ones. These opened sites were predominantly found in DNA regions containing binding sites for the SIX2 protein. This suggests that the inhibition of the androgen receptor alters gene regulation, allowing the expression of previously silenced genes and altering cell states.
SIX2 Protein’s Role Beyond Embryogenesis
The SIX2 protein, typically active during embryogenesis to maintain undifferentiated stem cells, was found to play a role in prostate cancer cell plasticity and malignancy. The study revealed that SIX2 could regulate differentiation in prostate cancer cells lacking the androgen receptor. Notably, enzalutamide treatment increased SIX2 gene activity in these cells. “Silencing of the SIX2 gene, on the other hand, significantly reduced the malignancy of cancer cells that are resistant to hormonal therapies,” explained Doctoral Researcher Noora Leppänen.
The researchers discovered that silencing the SIX2 gene markedly reduced the stem cell-like state, migration, invasion, and metastasis of cancer cells. Additionally, experiments on zebrafish showed decreased cell division and cancer spread, underscoring the potential of targeting SIX2 in drug development for metastatic, hormone therapy-resistant prostate cancer.
Future Directions in Targeting SIX2
The findings suggest that inhibiting SIX2 activity could be a promising strategy for treating or preventing metastatic prostate cancer resistant to hormone therapies. As Academy Research Fellow Kirsi Ketola stated, “It is important to identify the key factors contributing to treatment resistance in prostate cancer and how cancer cells change their degree of differentiation to find new targets for therapies. This could even lead to the discovery of a cure for these currently lethal types of cancer.”
Publication Details
Noora Leppänen, Heidi Kaljunen, Eerika Takala, Roosa Kaarijärvi, Petri I Mäkinen, Seppo Ylä-Herttuala, Ilkka Paatero, Ville Paakinaho, Kirsi Ketola, SIX2 promotes cell plasticity via Wnt/β-catenin signalling in androgen receptor independent prostate cancer, Nucleic Acids Research, 2024;, gkae206, https://doi.org/10.1093/nar/gkae206
Prostate cancer, the most prevalent cancer in men and the second leading cause of cancer mortality in Western countries, is often treated with androgen receptor inhibition therapies. Despite initial effectiveness, cancer cells can develop resistance, leading to castration-resistant prostate cancer. The ability of cancer cells to revert to a stem cell-like state, known as plasticity, is suspected to underlie this resistance, though the contributing factors have remained elusive.
Investigating the Role of Chromatin in Treatment Resistance
The Ketola Lab at the University of Eastern Finland focused on uncovering new factors involved in treatment resistance. Their study examined chromatin openness in androgen-dependent prostate cancer cells treated with enzalutamide, an androgen receptor inhibitor. Chromatin, which packs DNA within cells, becomes looser in regions of active gene expression.
Following enzalutamide treatment, the researchers observed a significant increase in newly opened chromatin sites compared to newly closed ones. These opened sites were predominantly found in DNA regions containing binding sites for the SIX2 protein. This suggests that the inhibition of the androgen receptor alters gene regulation, allowing the expression of previously silenced genes and altering cell states.
SIX2 Protein’s Role Beyond Embryogenesis
The SIX2 protein, typically active during embryogenesis to maintain undifferentiated stem cells, was found to play a role in prostate cancer cell plasticity and malignancy. The study revealed that SIX2 could regulate differentiation in prostate cancer cells lacking the androgen receptor. Notably, enzalutamide treatment increased SIX2 gene activity in these cells. “Silencing of the SIX2 gene, on the other hand, significantly reduced the malignancy of cancer cells that are resistant to hormonal therapies,” explained Doctoral Researcher Noora Leppänen.
The researchers discovered that silencing the SIX2 gene markedly reduced the stem cell-like state, migration, invasion, and metastasis of cancer cells. Additionally, experiments on zebrafish showed decreased cell division and cancer spread, underscoring the potential of targeting SIX2 in drug development for metastatic, hormone therapy-resistant prostate cancer.
Future Directions in Targeting SIX2
The findings suggest that inhibiting SIX2 activity could be a promising strategy for treating or preventing metastatic prostate cancer resistant to hormone therapies. As Academy Research Fellow Kirsi Ketola stated, “It is important to identify the key factors contributing to treatment resistance in prostate cancer and how cancer cells change their degree of differentiation to find new targets for therapies. This could even lead to the discovery of a cure for these currently lethal types of cancer.”
Publication Details
Noora Leppänen, Heidi Kaljunen, Eerika Takala, Roosa Kaarijärvi, Petri I Mäkinen, Seppo Ylä-Herttuala, Ilkka Paatero, Ville Paakinaho, Kirsi Ketola, SIX2 promotes cell plasticity via Wnt/β-catenin signalling in androgen receptor independent prostate cancer, Nucleic Acids Research, 2024;, gkae206, https://doi.org/10.1093/nar/gkae206