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SMARCB1 loss induces druggable cyclin D1 deficiency via upregulation of MIR17HG in atypical teratoid rhabdoid tumors

ABSTRACT: Atypical teratoid rhabdoid tumor (ATRT) is a fatal pediatric malignancy of the central neural system lacking effective treatment options. It belongs to rhabdoid tumor family usually caused by biallelic inactivation of SMARCB1, encoding a key subunit of SWI/SNF chromatin remodelling complexes. Previous studies proposed that SMARCB1 loss drives rhabdoid tumor by promoting cell cycle through activating transcription of cyclin D1 while suppressing p16. However, low cyclin D1 protein expression is observed in most ATRT patient tumors. The underlying mechanism and therapeutic implication of this molecular trait remain unknown. Here, we show that SMARCB1 loss in ATRT leads to the reduction of cyclin D1 expression by upregulating MIR17HG, a microRNA (miRNA) cluster known to generate multiple miRNAs targeting CCND1. Furthermore, we find that this cyclin D1 deficiency in ATRT results in marked in vitro and in vivo sensitivity to the CDK4/6 inhibitor palbociclib as a single agent. Our study identifies a novel genetic interaction between SMARCB1 and MIR17HG in regulating cyclin D1 in ATRT and suggests a rationale to treat ATRT patients with FDA-approved CDK4/6 inhibitors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE147851 | GEO | 2020/06/08

REPOSITORIES: GEO

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Project description:Atypical teratoid/rhabdoid tumor (ATRT) is a highly malignant CNS neoplasm whichprimarily occurs in children under three years of age. Due to poor outcomes with intense and toxicmultimodality treatment, new therapies are urgently needed. Histone deacetylase inhibitors (HDIs)have been evaluated as novel agents for multiple malignancies and have been shown to function asradiosensitizers. They act as epigenetic modifiers and lead to re-expression of inappropriatelyrepressed genes, proteins, and cellular functions. Due to the underlying chromatin remodeling genemutation in ATRT, HDIs are ideal candidates for therapeutic evaluation. To evaluate the role of HDIsagainst ATRT in vitro, we assessed the effect of drug treatment on proliferation, apoptosis, and geneexpression. Additionally, we examined HDI pretreatment as a radiosensitization strategy for ATRT.MTS and clonogenic assays demonstrated that HDI treatment significantly reduces the proliferativecapacity of BT-12 and BT-16 ATRT cells. Also, the HDI SNDX-275 was able to induce apoptosis in bothcell lines and induced p21Waf1/Cip1 protein expression as measured by Western blot. Evaluation ofdifferential gene expression by microarray and pathway analysis after HDI treatment demonstratedalterations of several key ATRT cellular functions. Finally, we showed that HDI pretreatmenteffectively potentiates the effect of ionizing radiation on ATRT cells as measured by clonogenic assay.These findings suggest that the addition of HDIs to ATRT therapy may prove beneficial, especiallywhen administered in combination with current treatment modalities such as radiation. Keywords: ATRT; HDAC inhibitor; radiosensitization BT12 and BT16 cells were plated and subsequently treated for 24hr with IC25 concentrations of SNDX-275 (Sigma), at which time total RNA was collected. IC25 concentrations were calculated based on MTS assay.For BT12, the SNDX-275 IC25 was 1.4uM. For BT16, it was 0.44uM. The controls had DMSO added at equivalent volumes.

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SMARCB1 loss induces druggable cyclin D1 deficiency via upregulation of MIR17HG in atypical teratoid rhabdoid tumors

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