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Mol Cancer Res. 2019 Jan;17(1):186-198. doi: 10.1158/1541-7786.MCR-18-0485. Epub 2018 Sep 17.

p53 Function Is Compromised by Inhibitor 2 of Phosphatase 2A in Sonic Hedgehog Medulloblastoma.

Author information

1
Department of Pediatrics, Emory University, Atlanta, Georgia.
2
Winship Cancer Institute, Atlanta, Georgia.
3
Department of Biochemistry & Molecular Biology, Cumming School of Medicine, University of Calgary, Alberta, Canada.
4
The Hospital for Sick Children (SickKids), University of Toronto, Toronto, Ontario, Canada.
5
Department of Biochemistry, Emory University, Atlanta, Georgia.
6
Department of Pediatrics, Emory University, Atlanta, Georgia. anna.kenney@emory.edu.

Abstract

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-wildtype 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.

PMID:
30224541
PMCID:
PMC6318027
[Available on 2020-01-01]
DOI:
10.1158/1541-7786.MCR-18-0485

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