AUTHOR=Ceccarelli Manuela , D'Andrea Giorgio , Micheli Laura , Tirone Felice 

TITLE=Deletion of Btg1 Induces Prmt1-Dependent Apoptosis and Increased Stemness in Shh-Type Medulloblastoma Cells Without Affecting Tumor Frequency

JOURNAL=Frontiers in Oncology

VOLUME=10

YEAR=2020

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2020.00226

DOI=10.3389/fonc.2020.00226

ISSN=2234-943X

ABSTRACT=<p>About 30% of medulloblastomas (MBs), a tumor of the cerebellum, arise from cerebellar granule cell precursors (GCPs) undergoing transformation following activation of the Sonic hedgehog (Shh) pathway. To study this process, we generated a new MB model by crossing <italic>Patched1</italic> heterozygous (<italic>Ptch1</italic><sup>+/−</sup>) mice, which develop spontaneous Shh-type MBs, with mice lacking B-cell translocation gene 1 (<italic>Btg1</italic>), a regulator of cerebellar development. In MBs developing in <italic>Ptch1</italic><sup>+/−</sup> mice, deletion of <italic>Btg1</italic> does not alter tumor and lesion frequencies, nor affect the proliferation of neoplastic precursor cells. However, in both tumors and lesions arising in <italic>Ptch1</italic><sup>+/−</sup> mice, ablation of <italic>Btg1</italic> increases by about 25% the apoptotic neoplastic precursor cells, as judged by positivity to activated caspase-3. Moreover, although <italic>Btg1</italic> ablation in early postnatal GCPs, developing in the external granule cell layer, leads to a significant increase of proliferation, and decrease of differentiation, relative to wild-type, no synergy occurs with the <italic>Ptch1</italic><sup>+/−</sup> mutation. However, <italic>Btg1</italic> deletion greatly increases apoptosis in postnatal GCPs, with strong synergy between <italic>Btg1</italic>-null and <italic>Ptch1</italic><sup>+/−</sup> mutations. That pronounced increase of apoptosis observed in <italic>Ptch1</italic><sup>+/−</sup><italic>/Btg1</italic> knockout young or neoplastic GCPs may be responsible for the lack of effect of <italic>Btg1</italic> ablation on tumorigenesis. This increased apoptosis may be a consequence of increased expression of protein arginine methyltransferase 1 (Prmt1) protein that we observe in <italic>Btg1</italic> knockout/<italic>Ptch1</italic><sup>+/−</sup> MBs. In fact, apoptotic genes, such as <italic>BAD</italic>, are targets of Prmt1. Moreover, in <italic>Btg1</italic>-null MBs, we observed a two-fold increase of cells positive to CD15, which labels tumor stem cells, raising the possibility of activation of quiescent tumor cells, known for their role in long-term resistance to treatment and relapses. Thus, <italic>Btg1</italic> appears to play a role in cerebellar tumorigenesis by regulating the balance between apoptosis and proliferation during MB development, also influencing the number of tumor stem cells.</p>