Journal
NEOPLASIA
Volume 19, Issue 3, Pages 216-225Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.neo.2017.01.002
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Funding
- Padnos Fund for Innovative Cancer Research of the UM Comprehensive Cancer Center
- Michigan Institute for Clinical and Health Research
- National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) [UL1TR000433]
- M-Cubed Grant
- National Cancer Institute of the NIH [R01CA155360]
- Seattle Children's Neuro-oncology endowment
- UM Cancer Center [P30CA046592]
- UM Department of Pathology
- Bench to Bedside Translation Award
- Grants-in-Aid for Scientific Research [16H05220, 26252064] Funding Source: KAKEN
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Medulloblastoma is the most common malignant brain tumor in children. Therapeutic approaches to medulloblastoma (combination of surgery, radiotherapy, and chemotherapy) have led to significant improvements, but these are achieved at a high cost to quality of life. Alternative therapeutic approaches are needed. Genetic mutations leading to the activation of the Hedgehog pathway drive tumorigenesis in similar to 30% of medulloblastoma. In a yeast two-hybrid proteomic screen, we discovered a novel interaction between GLI1, a key transcription factor for the mediation of Hedgehog signals, and PIN1, a peptidylprolyl cis/trans isomerase that regulates the postphosphorylation fate of its targets. The GLI1/PIN1 interaction was validated by reciprocal pulldowns using epitope-tagged proteins in HEK293T cells as well as by co-immunoprecipiations of the endogenous proteins in a medulloblastoma cell line. Our results support a molecular model in which PIN1 promotes GLI1 protein abundance, thus contributing to the positive regulation of Hedgehog signals. Most importantly, in vivo functional analyses of Pin1 in the GFAP-tTA; TRE-SmoA1mousemodel of Hedgehog-driven medulloblastoma demonstrate that the loss of Pin1 impairs tumor development and dramatically increases survival. In summary, the discovery of the GLI1/ PIN1 interaction uncovers PIN1 as a novel therapeutic target in Hedgehog-driven medulloblastoma tumorigenesis.
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