SMARCB1 loss induces druggable cyclin D1 deficiency via upregulation of MIR17HG in atypical teratoid rhabdoid tumors.
Yibo XueXianbing ZhuBrian MeehanSriram VennetiDaniel MartinezGeneviève MorinRayelle I MaïgaHongbo ChenAndreas I PapadakisRadia M JohnsonMaureen J O'SullivanAnat Erdreich-EpsteinWalter H GotliebMorag ParkAlexander R JudkinsJerry PelletierWilliam D FoulkesJanusz RakSidong HuangPublished in: The Journal of pathology (2020)
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.
Keyphrases
- cell cycle
- cell proliferation
- genome wide
- long non coding rna
- poor prognosis
- pi k akt
- long noncoding rna
- transcription factor
- clinical trial
- fluorescent probe
- gene expression
- dna damage
- living cells
- intellectual disability
- replacement therapy
- systematic review
- drug delivery
- single molecule
- case report
- oxidative stress
- cell death
- metastatic breast cancer
- binding protein