Abstract
BackgroundGlioblastoma (GBM) is the most aggressive and lethal brain tumor. Although the histone deacetylase (HDAC)/transcription factor axis promotes growth in GBM, whether HDACs including HDAC6 are involved in modulating long non-coding RNAs (lncRNAs) to affect GBM malignancy remains obscure.MethodsIntegrative analysis of microarray and RNA-seq was performed to identify lncRNAs governed by HDAC6. Half-life measurement and RNA-protein pull-down assay combined with isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomic analysis were conducted to identify RNA modulators. The effect of LINC00461 on GBM malignancy was evaluated using animal models and cell proliferation-related assays. Functional analysis of the LINC00461 downstream networks was performed comprehensively using ingenuity pathway analysis and public databases.ResultsWe identified a lncRNA, LINC00461, which was substantially increased in stem-like/treatment-resistant GBM cells. LINC00461 was inversely correlated with the survival of mice-bearing GBM and it was stabilized by the interaction between HDAC6 and RNA-binding proteins (RBPs) such as carbon catabolite repression—negative on TATA-less (CCR4-NOT) core exoribonuclease subunit 6 and fused in sarcoma. Targeting LINC00461 using azaindolylsulfonamide, an HDAC6 inhibitor, decreased cell-division-related proteins via the lncRNA-microRNA (miRNA)-mRNA networks and caused cell-cycle arrest, thereby suppressing proliferation in parental and drug-resistant GBM cells and prolonging the survival of mice-bearing GBM.ConclusionsThis study sheds light on the role of LINC00461 in GBM malignancy and provides a novel therapeutic strategy for targeting the HDAC6/RBP/LINC00461 axis and its downstream effectors in patients with GBM.
Highlights
Glioblastoma (GBM) is the most aggressive and lethal brain tumor
HDAC6 inhibition significantly decreases LINC00461 expression To determine whether HDAC6 affects long non-coding RNAs (lncRNAs) regulation, we analyzed the expression levels of 9445 lncRNAs using microarray
The results are shown as mean ± SEM for triplicate samples in each group and trichostatin A, led to a decrease in the interaction of HDAC6 and CCR4-NOT core exoribonuclease subunit 6 (CNOT6) in cells (Fig. S3A), suggesting that deacetylase activity is essential for HDAC6 to bind CNOT6, causing changes in the deadenylase activation
Summary
The histone deacetylase (HDAC)/transcription factor axis promotes growth in GBM, whether HDACs including HDAC6 are involved in modulat‐ ing long non-coding RNAs (lncRNAs) to affect GBM malignancy remains obscure. Glioblastoma (GBM) has a poor prognosis and remains incurable, despite aggressive treatment options including surgery, radiation therapy, and first-line chemotherapy with the drug temozolomide (TMZ). Less than 5% of the patients with GBM survive for 5 years following diagnosis. Previous studies have revealed that GBM frequently harbors different gene expression patterns, causing patients to exhibit diverse clinical characteristics, survival times, and responses to treatment [2, 3]. Identification of lncRNA as a potential target for treating patients with GBM is urgently needed
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