AMBRA1 phosphorylation by CDK1 and PLK1 regulates mitotic spindle orientation.

AMBRA1 is a crucial factor for nervous system development, and its function has been mainly associated with autophagy. It has been also linked to cell proliferation control, through its ability to regulate c-Myc and D-type cyclins protein levels, thus regulating G1-S transition. However, it remains still unknown whether AMBRA1 is differentially regulated during the cell cycle, and if this pro-autophagy protein exerts a direct role in controlling mitosis too. Here we show that AMBRA1 is phosphorylated during mitosis on multiple sites by CDK1 and PLK1, two mitotic kinases. Moreover, we demonstrate that AMBRA1 phosphorylation at mitosis is required for a proper spindle function and orientation, driven by NUMA1 protein. Indeed, we show that the localization and/or dynamics of NUMA1 are strictly dependent on AMBRA1 presence, phosphorylation and binding ability. Since spindle orientation is critical for tissue morphogenesis and differentiation, our findings could account for an additional role of AMBRA1 in development and cancer ontogenesis.

Bromodomain and Extraterminal Domain (BET) Protein Inhibition Hinders Glioblastoma Progression by Inducing Autophagy-Dependent Differentiation.

Glioblastoma multiforme (GBM) is the most common and aggressive type of malignant primary brain tumor, and it is characterized by a high recurrence incidence and poor prognosis due to the presence of a highly heterogeneous mass of stem cells with self-renewal capacity and stemness maintenance ability. In recent years, the epigenetic landscape of GBM has been explored and many epigenetic alterations have been investigated. Among the investigated epigenetic abnormalities, the bromodomain and extra-terminal domain (BET) chromatin readers have been found to be significantly overexpressed in GBM. In this work, we investigated the effects of BET protein inhibition on GBM cell reprogramming. We found that the pan-BET pharmacological inhibitor JQ1 was able to promote a differentiation program in GBM cells, thus impairing cell proliferation and enhancing the toxicity of the drug Temozolomide (TMZ). Notably, the pro-differentiation capability of JQ1 was prevented in autophagy-defective models, suggesting that autophagy activation is necessary for BET protein activity in regulating glioma cell fate. Given the growing interest in epigenetic therapy, our results further support the possibility of introducing a BET-based approach in GBM clinical management.

Regulation of Cell Plasticity by Bromodomain and Extraterminal Domain (BET) Proteins: A New Perspective in Glioblastoma Therapy.

BET proteins are a family of multifunctional epigenetic readers, mainly involved in transcriptional regulation through chromatin modelling. Transcriptome handling ability of BET proteins suggests a key role in the modulation of cell plasticity, both in fate decision and in lineage commitment during embryonic development and in pathogenic conditions, including cancerogenesis. Glioblastoma is the most aggressive form of glioma, characterized by a very poor prognosis despite the application of a multimodal therapy. Recently, new insights are emerging about the glioblastoma cellular origin, leading to the hypothesis that several putative mechanisms occur during gliomagenesis. Interestingly, epigenome dysregulation associated with loss of cellular identity and functions are emerging as crucial features of glioblastoma pathogenesis. Therefore, the emerging roles of BET protein in glioblastoma onco-biology and the compelling demand for more effective therapeutic strategies suggest that BET family members could be promising targets for translational breakthroughs in glioblastoma treatment. Primarily, "Reprogramming Therapy", which is aimed at reverting the malignant phenotype, is now considered a promising strategy for GBM therapy.