The BMI1 proto-oncogene, polycomb ring finger
protein (BMI1) is a key component of the epigenetic polycomb repressor complex 1, and has been associated with aggressive behaviour and chemotherapeutic resistance in various malignances including human
gliomas. Similar to humans, spontaneous canine
gliomas carry a poor prognosis with limited therapeutic options. BMI1 expression and the effects of BMI1 inhibition have not been evaluated in canine
gliomas. Here, we demonstrate that BMI1 is highly expressed in canine
gliomas. Although increased BMI1
protein expression correlated with higher
glioma grade in western blot assays, this correlation was not observed in a larger sample set using immunohistochemical analysis. The BMI1 inhibitor,
PTC-209, suppressed BMI1 expression in established canine
glioma cell lines and resulted in antiproliferative activity when used alone and in combination with chemotherapeutic agents.
PTC-209 targeting of BMI1 activated the
retinoblastoma (RB) pathway through downregulation of total and phosphorylated RB, independent of INK4A/ARF signalling, likely through BMI1-inhibition mediated upregulation of p21. These data support the rationale for targeting of BMI1 signalling and the use of canine
glioma as a translational therapeutic model for human disease.