Abstract Diffuse Intrinsic Pontine Glioma (DIPG) is a devastating pediatric brain malignancy characterized by its aggressive nature and dismal prognosis, with a median survival of less than one year. This underscores the urgent need for innovative therapeutic strategies. BMI-1, a proto-oncogene, and a pivotal component of the Polycomb Repressive Complex 1 (PRC1), is integral to cellular development, stemness, and self-renewal. We have previously shown that BMI-1 is a potential therapeutic target in DIPG. However, its role in tumorigenesis and tumor progression remains inadequately characterized. This study investigates the molecular pathways underpinning BMI-1’s function during M phase, with a particular focus on its PRC1-independent function. Our investigation revealed that PTC596, a potent modulator of BMI-1, induces significant cellular changes, including chromosome scattering, M phase cell-cycle arrest, BMI-1 phosphorylation, and translocation to the cytoplasm, ultimately disrupting PRC1 canonical functions and inducing cell death. Specifically, we identified that BMI-1 phosphorylation occurs at S316 residue within the PEST domain during M phase, driven by the CDK-AKT signaling cascade. Molecular simulation modeling indicated that phosphorylation at this site induces structural reconfigurations in BMI-1, with functional implications. Notably, IP-MASS analysis demonstrated that S316 phosphorylation shifts BMI-1’s binding landscape, enhancing its interactions with ribosomal proteins, mRNA processing factors, and mitochondrial proteins. Furthermore, BMI-1 was found to colocalize with COX4 in mitochondria during M phase, highlighting a potential novel, PRC1-independent role in mitochondrial regulation. To further elucidate the functional impact of S316 phosphorylation, we generated BMI-1 mutants (S316A and S316D) for comparative analyses of their effects on BMI-1 localization, cell viability and M phase progression. Collectively, these findings underscore a critical survival role for BMI-1 during M phase in DIPG. Targeting the phosphorylation-dependent pathways of BMI-1 may offer a promising avenue for therapeutic intervention in DIPG.
Pang et al. (Fri,) studied this question.
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