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SMARCB1 loss induces druggable cyclin D1 deficiency via upregulation of MIR17HG in atypical teratoid rhabdoid tumors
Author(s) -
Xue Yibo,
Zhu Xianbing,
Meehan Brian,
Venneti Sriram,
Martinez Daniel,
Morin Geneviève,
Maïga Rayelle I,
Chen Hongbo,
Papadakis Andreas I,
Johnson Radia M,
O'Sullivan Maureen J,
ErdreichEpstein Anat,
Gotlieb Walter H,
Park Morag,
Judkins Alexander R,
Pelletier Jerry,
Foulkes William D,
Rak Janusz,
Huang Sidong
Publication year - 2020
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.5493
Subject(s) - smarcb1 , cyclin d1 , atypical teratoid rhabdoid tumor , cancer research , cyclin b , downregulation and upregulation , microrna , biology , cell cycle , epigenetics , cancer , genetics , chromatin remodeling , gene , medulloblastoma
Atypical teratoid rhabdoid tumor (ATRT) is a fatal pediatric malignancy of the central neural system lacking effective treatment options. It belongs to the rhabdoid tumor family and is usually caused by biallelic inactivation of SMARCB1 , encoding a key subunit of SWI/SNF chromatin remodeling 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. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.