Journal
MOLECULAR CANCER RESEARCH
Volume 17, Issue 1, Pages 186-198Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-18-0485
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Funding
- NINDS [R01NS061070]
- NCI Winship Cancer Institute P30 Center grant [CA138292]
- NCI [R01CA57327]
- NIH [R01CA148699, R01CA159859]
- Pediatric Brain Tumour Foundation
- Terry Fox Research Institute
- Canadian Institutes of Health Research
- Cure Search Foundation
- b.r.a.i.n.child
- Meagan's Walk
- Genome Canada
- Genome BC
- Ontario Institute for Cancer Research, Canadian Cancer Society Research Institute Impact
- SU2C - St. Baldrick's Pediatric Dream Team Translational Research grant [SU2C-AACR-DT11-13]
- SU2C Canada Cancer Stem Cell Dream Team Research Funding by the Government of Canada through Genome Canada [SU2C-AACR-DT-19-15]
- Canadian Institute of Health Research
- Ontario Institute for Cancer Research, through the Government of Ontario
- American Association for Cancer Research, the Scientific Partner of SU2C
- American Association for Cancer Research International - Canada, the Scientific Partner of SU2C Canada
- Garron Family Chair in Childhood Cancer Research at the Hospital for Sick Children
- University of Toronto
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Medulloblastomas, the most common malignant pediatric brain tumors, have been genetically defined into four subclasses, namely WNT-activated, Sonic Hedgehog (SHH)-activated, Group 3, and Group 4. Approximately 30% of medulloblastomas have aberrant SHH signaling and thus are referred to as SHH-activated medulloblastoma. The tumor suppressor gene TP53 has been recently recognized as a prognostic marker for patients with SHH-activated medulloblastoma; patients with mutant TP53 have a significantly worse outcome than those with wild-type TP53. It remains unknown whether p53 activity is impaired in SHH-activated, wild-type TP53 medulloblastoma, which is about 80% of the SHH-activated medulloblastomas. Utilizing the homozygous NeuroD2:SmoA1 mouse model with wild-type Trp53, which recapitulates human SHH-activated medulloblastoma, it was discovered that the endogenous Inhibitor 2 of Protein Phosphatase 2A (SET/I2PP2A) suppresses p53 function by promoting accumulation of phospho-MDM2 (S166), an active form of MDM2 that negatively regulates p53. Knockdown of I2PP2A in SmoA1 primary medulloblastoma cells reduced viability and proliferation in a p53-dependent manner, indicating the oncogenic role of I2PP2A. Importantly, this mechanism is conserved in the human medulloblastoma cell line ONS76 with wild-type TP53. Taken together, these findings indicate that p53 activity is inhibited by I2PP2A upstream of PP2A in SHH-activated and TP53-wild type medulloblastomas. Implications: This study suggests that I2PP2A represents a novel therapeutic option and its targeting could improve the effectiveness of current therapeutic regimens for SHH-activated or other subclasses of medulloblastoma with wild-type TP53.
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