| Summary: | <p>Stem cells are characterised by their ability to continuously self-renew and differentiate into various lineages. This balance is tightly controlled by intrinsic and extrinsic factors that maintain normal development and tissue homoeostasis. The dysregu- lation of these factors is associated with oncogenesis and is extensively studied in the context of treatment resistance and tumour reoccurrence. Stem and cancer cells share the ability to indefinitely self-renew and therefore it stands to reason that these cells harbour similar underlying regulatory processes. Stem cells that are unable to differentiate are widely described as cancer initiating (or cancer stem) cells and their inability to differentiate is therefore heavily investigated as a therapeutic target. A crucial signalling pathway regulating pluripotency and proliferation in stem and can- cer cells is the Hippo tumour suppressor pathway. RASSF1A, a key regulator of the Hippo pathway, is frequently methylated in numerous brain/central nervous system (CNS) malignancies, indicating that a potential deregulation of stem cells may drive the association with poorer prognosis. In this work we demonstrate that RASSF1A mediates the localisation of suppressor of variegation 3-9 homologue 1 (SUV39H1), a histone methyltransferase that catalyses the trimethylation of histone 3 lysine 9 (H3K9me3). H3K9me3, a heterochromatin mark that stably represses genes during differentiation, is reduced with loss of RASSF1A, leading to impaired neural differentiation of stem cells. Our findings suggest that the epigenetic loss of RASSF1A therefore contributes to a dedifferentiated phenotype in cancer.</p>
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