Medulloblastoma is the most common malignant pediatric brain tumor. While current treatments have improved survival, survivors face high risk of recurrence and significant long-term quality of life issues. These side effects result from a failure of the current treatment approaches to target tumor cells and spare the normal brain of young patients. Thus, targeted therapies are desperately needed. However, this requires a better understanding of disease biology and the identification of disease-specific molecular events. Medulloblastomas arise from a developmental imbalance between proliferation and neuronal differentiation in cerebellar progenitor cells. Medulloblastomas often show abnormally high expression of the RE1 Silencing Transcription Factor (REST), a repressor of neuronal differentiation. REST expression is associated with blockade of neuronal differentiation and a poor prognostic significance for patients. The requirement for REST in medulloblastoma progression and maintenance was shown in murine orthotopic models. However, mechanistic details were lacking. REST was recently implicated in the control of cell proliferation in medulloblastoma and in cerebellar progenitor cells. An increase in REST expression facilitated excessive degradation of the cyclin dependent kinase inhibitor (CDKI) p27 in tumor cells by repressing the transcription of a novel p27-specific deubiquitylase, USP37. The expression of p27 was significantly correlated with USP37 and REST in human medulloblastoma samples. Constitutive expression of wild type USP37, but not a catalytically inactive mutant rescued defects in p27 behavior, blocked proliferation and promoted neuronal differentiation in medulloblastoma cells. These data not only link REST to p27 and the control of cell proliferation in vitro, but also implicate USP37 in this process. The current application will study this newly identified pathway in deregulation of cell proliferation and tumor development in mouse models. The overall hypothesis of this proposal is that REST-mediated repression of USP37 and the consequent decline in p27 levels contributes to medulloblastoma development by causing a failure of cell cycle exit and perturbing the balance between cell proliferation and neuronal differentiation.
Aim1 of the proposed studies will determine if REST and USP37 are important for loss of proliferative control and tumor formation in mice with p27- deficiency.
Aim 2, will assess if p27 is necessary and sufficient for USP37-dependent brake on cell proliferation and tumor development.
Aim 3 will examine the mechanism by which REST controls USP37 transcription. These studies will provide a better understanding of the newly identified relationship between REST, USP37 and p27 in the control of cell proliferation and medulloblastoma development and set the stage for future therapeutic targeting of this pathway.
REST is a transcriptional repressor of neuronal differentiation genes. Its aberrant expression in medulloblastoma blocks neuronal differentiation and promotes uncontrolled proliferation. The proposed experiments will study contribution of the novel REST-USP37-p27 connection to medulloblastoma cell proliferation and tumorigenesis.