Abstract
Medulloblastoma, the most common pediatric brain tumor, is thought to arise from deregulated proliferation of cerebellar granule precursor (CGP) cells. Sonic hedgehog (Shh) is the primary mitogen that regulates proliferation of CGP cells during the early stages of postnatal cerebellum development. Aberrant activation of Shh signaling during this time has been associated with hyperplasia of CGP cells and eventually may lead to the development of medulloblastoma. The molecular targets of Shh signaling involved in medulloblastoma formation are still not well-understood. Here, we show that Shh regulates sustained activation of histone deacetylases (HDACs) and that this activity is required for continued proliferation of CGP cells. Suppression of HDAC activity not only blocked the Shh-induced CGP proliferation in primary cell cultures, but also ameliorated aberrant CGP proliferation at the external germinal layer (EGL) in a medulloblastoma mouse model. Increased levels of mRNA and protein of several HDAC family members were found in medulloblastoma compared to wild type cerebellum suggesting that HDAC activity is required for the survival/progression of tumor cells. The identification of a role of HDACs in the early steps of medulloblastoma formation suggests there may be a therapeutic potential for HDAC inhibitors in this disease.
Highlights
Postnatal development of the cerebellum progresses along with the migration and proliferation of neuronal precursor cells which give rise to granule, Purkinje, Golgi, stellate and basket neurons [1]
In an effort to further understand the role of histone deacetylases (HDACs) in medulloblastoma development, we compared protein and mRNA levels of individual HDAC family members in lysates obtained from wild type cerebellum to healthy cerebellum and medulloblastoma tumors from Smo/Smo transgenic mice
We show that that pharmacological inhibition of HDAC activity during early postnatal development of the cerebellum could block Sonic hedgehog (Shh)-induced cerebellar granular precursor (CGP) hyperplasia in the Smo/Smo mice suggesting that HDAC inhibitors may be especially beneficial early on or in very young children for therapeutic intervention in medulloblastoma
Summary
Postnatal development of the cerebellum progresses along with the migration and proliferation of neuronal precursor cells which give rise to granule, Purkinje, Golgi, stellate and basket neurons [1]. The most abundant are cerebellar granular precursor (CGP) cells which originate and migrate tangentially from the rhombic lip of the dorsal hindbrain to form the external germinal layer (EGL). Purkinje cells are the sole output of the computational circuitry of the cerebellar cortex, and secrete soluble Sonic hedgehog (Shh) which induces the initial proliferation of CGP cells at the EGL during development [3]. Activation of this pathway is initiated by binding of Shh to the extracellular receptor Patched (Ptch), thereby relieving the inhibition on Smoothened (Smo) allowing for transmission of downstream signals [4]. Underscoring its importance during medulloblastoma progression, mutations in the Shh signaling pathway, including Ptch, Smo and the downstream gene Suppressor of fused (Sufu) have been found in approximately 25–30% of medulloblastoma cases [6]
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