KCTD15 inhibits the Hedgehog pathway in Medulloblastoma cells by increasing protein levels of the oncosuppressor KCASH2

Eleonora Spiombi,Gianluca Canettieri,Elisabetta Ferretti,Evelina Miele,Giuseppina De Feudis,Francesca Fabretti,Paola Infante,Daniele Guardavaccaro,Lucia Di Marcotullio,Danilo Cucchi,Alberto Gulino,Annapaola Angrisani,Marella Maroder,Laura Di Magno,Roberto Magliozzi,Marta Moretti,Agnese Pò ,Simone Fonte,Mariapaola Izzo,Enrico De Smaele

doi:10.1038/s41389-019-0175-6

Abstract

Medulloblastoma (MB) is the most common malignant childhood brain tumor. About 30% of all MBs belong to the I molecular subgroup, characterized by constitutive activation of the Sonic Hedgehog (Hh) pathway. The Hh pathway is involved in several fundamental processes during embryogenesis and in adult life and its deregulation may lead to cerebellar tumorigenesis. Indeed, Hh activity must be maintained via a complex network of activating and repressor signals. One of these repressor signals is KCASH2, belonging to the KCASH family of protein, which acts as negative regulators of the Hedgehog signaling pathway during cerebellar development and differentiation. KCASH2 leads HDAC1 to degradation, allowing hyperacetylation and inhibition of transcriptional activity of Gli1, the main effector of the Hh pathway. In turn, the KCASH2 loss leads to persistent Hh activity and eventually tumorigenesis. In order to better characterize the physiologic role and modulation mechanisms of KCASH2, we have searched through a proteomic approach for new KCASH2 interactors, identifying Potassium Channel Tetramerization Domain Containing 15 (KCTD15). KCTD15 is able to directly interact with KCASH2, through its BTB/POZ domain. This interaction leads to increase KCASH2 stability which implies a reduction of the Hh pathway activity and a reduction of Hh-dependent MB cells proliferation. Here we report the identification of KCTD15 as a novel player in the complex network of regulatory proteins, which modulate Hh pathway, this could be a promising new target for therapeutic approach against MB.

Highlights

Medulloblastoma (MB) is the most common malignant brain tumor in children, representing nearly 20% of all childhood brain cancers[1]
KCTD15 function has been described mostly in neural crest[16], other data indicate that it is expressed in different adult mouse and human tissues, including adult brain and cerebellum[17,18,19] suggesting a potential interplay with KCASH2, which has been described to play an important role in Hh regulation during cerebellar development and differentiation[13]
Because of the high homology within the KCASH proteins and their shared functions, we evaluated if KCTD15 interacts with the other KCASH proteins: KCASH1 and KCASH3

Summary

Introduction

Medulloblastoma (MB) is the most common malignant brain tumor in children, representing nearly 20% of all childhood brain cancers[1]. Transcriptional and molecular characterization of MBs has led to their classification into four primary subgroups: (I) SHH-activated; (II) WNTactivated; (III) Group 3; and (IV) Group 42–4. MBs represents about 30% of all MBs and is characterized by constitutive activation of the Sonic Hedgehog (Hh) signaling pathway. The Hh pathway is involved in fundamental processes during embryogenesis and in adult life, including cell proliferation, differentiation and morphogenesis, stem cell maintenance and regeneration[5,6], and in tumorigenesis. Hh induces the growth of the external granule layer (EGL), which is mainly formed by Granule Cell Progenitors (GCPs)[7,8,9]. At the completion of the proliferative stage, Hh signal must be turned off, GCPs migrate to the cerebellar internal granule layer (IGL) and differentiate in mature neurons.

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