Geminin deficiency enhances survival in a murine medulloblastoma model by inducing apoptosis of preneoplastic granule neuron precursors

Abstract

Medulloblastoma is the most common malignant brain cancer of childhood. Further understanding of tumorigenic mechanisms may define new therapeutic targets. Geminin maintains genome fidelity by controlling re-initiation of DNA replication within a cell cycle. In some contexts, Geminin inhibition induces cancer-selective cell cycle arrest and apoptosis and/or sensitizes cancer cells to Topoisomerase IIα inhibitors such as etoposide, which is used in combination chemotherapies for medulloblastoma. However, Geminin's potential role in medulloblastoma tumorigenesis remained undefined. Here, we found that Geminin is highly expressed in human and mouse medulloblastomas and in murine granule neuron precursor (GNP) cells during cerebellar development. Conditional Geminin loss significantly enhanced survival in the SmoA1 mouse medulloblastoma model. Geminin loss in this model also reduced numbers of preneoplastic GNPs persisting at one postnatal month, while at two postnatal weeks these cells exhibited an elevated DNA damage response and apoptosis. Geminin knockdown likewise impaired human medulloblastoma cell growth, activating G2 checkpoint and DNA damage response pathways, triggering spontaneous apoptosis, and enhancing G2 accumulation of cells in response to etoposide treatment. Together, these data suggest preneoplastic and cancer cell-selective roles for Geminin in medulloblastoma, and suggest that targeting Geminin may impair tumor growth and enhance responsiveness to Topoisomerase IIα-directed chemotherapies.

Intrinsic neural stem cell properties define brain hypersensitivity to genotoxic stress

“…Whereas GMNN plays a critical role in the regulation of DNA replication licensing, it is also implicated in cell-fate commitment by modulating the chromatin state and the transcriptional activation of lineage-specific genes ( Del Bene et al., 2004 ; Karamitros et al., 2015 ; Kroll et al., 1998 ; Luo et al., 2004 ; Patterson et al., 2014 ; Seo et al., 2005 ; Yellajoshyula et al., 2011 ). Interestingly, previous in vivo studies in the hematopoietic system ( Karamitros et al., 2010 , 2015 ) and in the adult brain ( Sankar et al., 2017 ; Schultz et al., 2011 ) support the idea that GMNN functions depend on the cellular context. Here, by using two distinct transgenic animal models, we describe the differential response of NECs and neurogenic NPs to GMNN depletion.…”