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

• Published in: Molecular cancer research Vol. 17; no. 1; pp. 186 - 198
• Main Authors: Wei, Yun, Maximov, Victor, Morrissy, Sorana A, Taylor, Michael D, Pallas, David C, Kenney, Anna Marie
• Format: Journal Article
• Language: English
• Published: United States 01.01.2019
• Subjects: Adult; Animals; Cell Line, Tumor; Cerebellar Neoplasms - genetics; Cerebellar Neoplasms - metabolism; Cerebellar Neoplasms - pathology; DNA-Binding Proteins - antagonists & inhibitors; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; Gene Knockdown Techniques; Hedgehog Proteins - metabolism; Histone Chaperones - antagonists & inhibitors; Histone Chaperones - genetics; Histone Chaperones - metabolism; Humans; Medulloblastoma - genetics; Medulloblastoma - metabolism; Medulloblastoma - pathology; Mice; Peptides - pharmacology; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Up-Regulation
• ISSN: 1541-7786; 1557-3125
• DOI: 10.1158/1541-7786.MCR-18-0485

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 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 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 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 -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.