REST Is a Novel Prognostic Factor and Therapeutic Target for Medulloblastoma

Abstract

Medulloblastoma is a malignant pediatric brain tumor. Current treatment following patient stratification into standard and high-risk groups using clinical features, has improved survival. However, a subset of patients with standard-risk features have unanticipated aggressive disease, underscoring the need for a better understanding of tumor biology and development of novel treatments. Poor differentiation, a hallmark of medulloblastomas is associated with elevated expression levels of the repressor of neuronal differentiation REST. Here, we assessed if elevated REST expression levels had prognostic significance and if its pharmacological manipulation would promote neurogenesis and block tumor cell growth. REST levels in patient tumors were measured by immunohistochemistry (IHC) and stratified into low/moderate- (+/++/+++) and high-REST (+++++) groups. Kaplan-Meier curves revealed that patients with high-REST tumors had worse overall and event-free survival compared to patients with REST-negative or REST-low tumors. Since histone deacetylases (HDACs), are required for REST-dependent repression of neurogenesis, we evaluated a panel of HDAC inhibitors (HDACIs) for their effects on growth and differentiation of established and primary REST-positive cell lines. MS-275, trichostatin-A (TSA), valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA) upregulated expression of the REST-target neuronal differentiation gene, Syn1, suggesting a potential effect of these HDACIs on REST function. Interestingly, VPA and TSA substantially increased histone acetylation at the REST promoter and activated its transcription, whereas SAHA unexpectedly promoted its proteasomal degradation. A REST-dependent decrease in cell growth was also observed following SAHA treatment. Thus, our studies suggest that HDACIs may have therapeutic potential for patients with REST-positive tumors. This warrants further investigation.

NRSF is an essential mediator for the neuroprotection of trichostatin A in the MPTP mouse model of Parkinson's disease

“…Utilization of HDACIs to protect dopamine neurons against the stresses of MPTP and lipopolysaccharide (LPS) has also been determined (Gardian et al, 2004, Chen et al, 2007, Wu et al, 2008, Faraco et al, 2009, Kidd and Schneider, 2011 Recently, it has been reported that elevated expression levels of NRSF are associated with the poor differentiation of medulloblastoma, a specific form of malignant pediatric brain tumors (Taylor et al, 2012). were mounted on glass slides and air dried.…”

Downregulation of Ca2+-Activated Cl− Channel TMEM16A by the Inhibition of Histone Deacetylase in TMEM16A-Expressing Cancer Cells

“…Due to the epigenetic modification, HDACi are able to upregulate tumor suppressor gene expression, resulting in inhibited cancer cell viability (Gui et al, 2004). For example, several HDACi upregulate the tumor suppressor p53 (Kim et al, 2001) and the repressor element 1-silencing transcription factor (also called neuron-restrictive silencer factor) (Taylor et al, 2012) in cancer cells. These suppressors play important roles in repressing ion channel expression.…”

REST Final-Exon-Truncating Mutations Cause Hereditary Gingival Fibromatosis

“…18,[29][30][31][32][33][34][35][36][37][38][39][40] Recently, mutations in REST have been shown to predispose to Wilms tumor (MIM: 616806). 41 The identified REST mutations in individuals with Wilms tumor were clustered within the zinc-finger DNA-binding domain of REST ( Figure 2C).…”