Long Noncoding RNA <i>SChLAP1</i> Forms a Growth-Promoting Complex with HNRNPL in Human Glioblastoma through Stabilization of ACTN4 and Activation of NF-κB Signaling.

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 (<i>SChLAP1</i>), 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 <i>SChLAP1</i> 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 <i>SChLAP1</i> and associated proteins in human gliomas. Proteins complexed with <i>SChLAP1</i> were identified using RNA pull-down and mass spectrometry. Lentiviral constructs were used for functional analysis <i>in vitro</i> and <i>in vivo</i>. <i>SChLAP1</i> was increased in primary GBM samples and cell lines, and knockdown of the lncRNA suppressed growth. <i>SChLAP1</i> 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). <i>ACTN4</i> was also highly expressed in primary GBM samples and was associated with poorer overall survival in glioma patients. The <i>SChLAP1</i>-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 <i>SChLAP1</i> as a driver of GBM growth as well as a potential therapeutic target in treatment of the disease.