Loss of Phosphatase CTDNEP1 Initiates Malignant Medulloblastoma by Unleashing Myc Activation and Destabilizing the Genome

ABSTRACT: we report the mutations in the serine/threonine-phosphatase CTDNEP1 and abnormally low levels of CTDNEP1 expression, predominantly in Group-3 MBs, correlate with c-MYC amplification and poor prognosis. We found that CTDNEP1 phosphatase activity negatively regulates c-MYC stability and tumor cell proliferation. Further, deletion of Ctdnep1 in neural progenitors in mice induced p53 loss, activation of DNA damage responses, and chromosomal aneuploidy with c-MYC upregulation, causing transformation into Group 3-like tumors. Loss of Ctdnep1 further activated M-phase-promoting protein complexes and promoted mitotic dysregulation. We generated the genome-wide chromatin-state maps and transcriptome of mouse cKO-Ctdnep1 NPCs and its control. Co-targeting c-MYC and mitotic checkpoints inhibited the tumorigenic growth of Group 3-like MB tumors and prolonged animal survival. This study demonstrates a previously uncharacterized tumor suppressor function for the phosphatase CTDNEP1 through dysregulation of c-MYC, mitosis and maintenance of chromosome stability. Overall design: Examination of different RNA-seq, ATAC-seq and low coverage WGS in 2 cell mouse cells. RNA-seq in human stable cell lines

INSTRUMENT(S): Illumina HiSeq 2500 (Homo sapiens)

SUBMITTER: Zaili Luo  

PROVIDER: GSE145921 | GEO | 2020-03-04

REPOSITORIES: GEO