Long Noncoding RNA SChLAP1 forms a Growth-Promoting Complex with HNRNPL in human glioblastoma through stabilization of ACTN4 and activation of NF-κB signaling.

  • NORLUX Neuro-Oncology Laboratory
November 15, 2019 By:
  • Ji J
  • Xu R
  • Ding K
  • Bao G
  • Zhang X
  • Huang B
  • Martinez A
  • Wang X
  • Li G
  • Miletic H
  • Thorsen F
  • Bjerkvig R
  • Xiang L
  • Han B
  • Chen A
  • Li X
  • Wang J.

PURPOSE: 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). EXPERIMENTAL DESIGN: 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. RESULTS: 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-kappaB and activation of NF-kappaB signaling, a pathway associated with cancer development. CONCLUSIONS: Our results implicated SChLAP1 as a driver of GBM growth as well as a potential therapeutic target in treatment of the disease.

2019 Nov. Clin Cancer Res.25(22):6868-6881. Epub 2019 Sep 6.
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