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

• Type of Material: Article
• Authors: Yun Wei, Emory University; Victor Maximov, Emory University; Sorana A. Morrissy, University of Calgary; Michael D. Taylor, University of Toronto; David Pallas, Emory University; Anna Kenney, Emory University
• Language: English
• Date: 2019-01-01
• Publisher: American Association for Cancer Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: 2018 American Association for Cancer Research.
• Final Published Version (URL): http://dx.doi.org/10.1158/1541-7786.MCR-18-0485
• Title of Journal or Parent Work: Molecular Cancer Research
• Volume: 17
• Issue: 1
• Start Page: 186
• End Page: 198
• Grant/Funding Information: Research Funding is administered by the American Association for Cancer Research International - Canada, the Scientific Partner of SU2C Canada. M.D.T. is supported by the Garron Family Chair in Childhood Cancer Research at the Hospital for Sick Children and the University of Toronto.; Research grants are administered by the American Association for Cancer Research, the Scientific Partner of SU2C. SU2C Canada is a Canadian Registered Charity (Reg. # 80550 6730 RR0001).; This work was supported by: NINDS R01NS061070 (AMK), NCI Winship Cancer Institute P30 Center Grant CA138292 (AMK, DCP), NCI R01CA57327 (DCP), M.D.T. was supported by NIH R01CA148699 and R01CA159859, The Pediatric Brain Tumour Foundation, The Terry Fox Research Institute, The Canadian Institutes of Health Research, The Cure Search Foundation, b.r.a.i.n.child, Meagan’s Walk, Genome Canada, Genome BC, and the Ontario Institute for Cancer Research, Canadian Cancer Society Research Institute Impact, and by SU2C - St. Baldrick’s Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT11–13) and SU2C Canada Cancer Stem Cell Dream Team Research Funding (SU2C-AACR-DT-19–15) provided by the Government of Canada through Genome Canada and the Canadian Institute of Health Research, with supplemental support from the Ontario Institute for Cancer Research, through funding provided by the Government of Ontario.
• Keywords: Life Sciences & Biomedicine; ACTIVATION; STEM-CELL; PP2A; TUMOR SUPPRESSION; PROTEIN; BRAIN-TUMORS; MDM2; SURVIVAL; PATHWAY; Science & Technology; PROGENITOR CELLS; Oncology; Cell Biology
• Research Categories: Health Sciences, Oncology; Biology, Cell

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.