Long Noncoding RNA Forms a Growth-Promoting Complex with HNRNPL in Human Glioblastoma Through Stabilization of ACTN4 and Activation of NF-κB Signaling

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 (), 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 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 and associated proteins in human gliomas. Proteins complexed with were identified using RNA pull-down and mass spectrometry. Lentiviral constructs were used for functional analysis and .

Results: was increased in primary GBM samples and cell lines, and knockdown of the lncRNA suppressed growth. 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). was also highly expressed in primary GBM samples and was associated with poorer overall survival in glioma patients. The -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.

Conclusions: Our results implicated as a driver of GBM growth as well as a potential therapeutic target in treatment of the disease.