Abstract
Long noncoding RNAs (lncRNA) have essential roles in diverse cellular processes, both in normal and diseased cell types, and thus have emerged as potential therapeutic targets. A specific member of this family, the SWI/SNF complex antagonist associated with prostate cancer 1 (SChLAP1), has been shown to promote aggressive prostate cancer growth by antagonizing the SWI/SNF complex and therefore serves as a biomarker for poor prognosis. Here, we investigated whether SChLAP1 plays a potential role in the development of human glioblastoma (GBM). RNA-ISH and IHC were performed on a tissue microarray to assess expression of SChLAP1 and associated proteins in human gliomas. Proteins complexed with SChLAP1 were identified using RNA pull-down and mass spectrometry. Lentiviral constructs were used for functional analysis in vitro and in vivo. SChLAP1 was increased in primary GBM samples and cell lines, and knockdown of the lncRNA suppressed growth. SChLAP1 was found to bind heterogeneous nuclear ribonucleoprotein L (HNRNPL), which stabilized the lncRNA and led to an enhanced interaction with the protein actinin alpha 4 (ACTN4). ACTN4 was also highly expressed in primary GBM samples and was associated with poorer overall survival in glioma patients. The SChLAP1-HNRNPL complex led to stabilization of ACTN4 through suppression of proteasomal degradation, which resulted in increased nuclear localization of the p65 subunit of NF-κB and activation of NF-κB signaling, a pathway associated with cancer development. Our results implicated SChLAP1 as a driver of GBM growth as well as a potential therapeutic target in treatment of the disease.
Highlights
Glioblastoma multiforme (GBM) accounts for nearly half of all primary brain tumors in adults [1]
SChLAP1 was increased in primary GBM samples and cell lines, and knockdown of the long noncoding RNAs (lncRNA) suppressed growth
The SChLAP1–heterogeneous nuclear ribonucleoprotein L (HNRNPL) complex led to stabilization of ACTN4 through suppression of proteasomal degradation, which resulted in increased nuclear localization of the p65 subunit of NF-kB and activation of NF-kB signaling, a pathway associated with cancer development
Summary
Glioblastoma multiforme (GBM) accounts for nearly half of all primary brain tumors in adults [1]. Rigorous molecular analysis has revealed many factors, such as EGF, IGF, TGFb, and downstream effectors involved in the uncontrolled growth of GBM [5]. Despite this knowledge, current treatment of GBM has limited efficacy, rendering the field desperate for novel therapeutic approaches. Somatic mutations clearly contribute to change in expression of many of these factors, a variety of other mechanisms, including dysregulation of noncoding RNAs, are recognized as having significant roles in the disease One class of these RNAs, the long noncoding RNAs (lncRNA), have been shown to regulate gene expression, as signals, decoys, guides, and scaffolds [6]. In the case of GBM, lncRNAs NEAT1 and TP73-AS1 promote cell growth through different mechanisms, mediating chromatin modification [8] and acting as a sponge for mir-142, respectively [9]
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