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

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.

KCTD15 is overexpressed in human childhood B-cell acute lymphoid leukemia

“…KCTD15 overexpression has never been reported to be linked to pathological states, although it has been indirectly associated with obesity in several literature reports and numerous studies showed an association between this gene and obesity 31,40–42 . It is also worth mentioning that the artificial overexpression of KCTD15 inhibits the neural crest formation 37 and that this protein is able to inhibit the Hedgehog pathway in medulloblastoma cells by increasing protein levels of the oncosuppressor KCASH2 43 .…”

Identification of key genes in lung adenocarcinoma based on a competing endogenous RNA network

“…The results of the Kaplan-Meier plotter analysis determined that the high expression groups of CD44, CCND3, NCALD and MACF1 had an improved prognosis compared with the low expression groups, while KCTD15 exhibited the opposite trend. To the best of our knowledge, KCTD15 upregulation has never been reported to be associated with pathological states, although it has been indirectly associated with several types of cancer, such as pleomorphic adenoma and medulloblastoma ( 39 , 40 ). The specific role of KCTD15 in LUAD should be investigated in future studies.…”

KCTD15 Protein Expression in Peripheral Blood and Acute Myeloid Leukemia

“…This is the case of the clade constituted by the highly homologous members KCTD1/KCTD15 [35]. Indeed, these highly homologous proteins play important roles in obesity [32][33][34], cancers [14,36], and scalp-ear-nipple syndrome [30,31]. Although KCTD1/KCTD15 biochemical function is largely unknown, also due to the lack of comprehensive structural data on these proteins [37,38], the above observations prompt for a role in the regulation of some basic process of cell life.…”