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HDAC6-LINC00461 pathway as a potential target for glioblastoma therapy

ABSTRACT: Background: Glioblastoma (GBM) is the most aggressive and lethal brain tumor. Although the histone deacetylase (HDAC)/Sp1 axis promotes growth and temozolomide (TMZ) resistance in glioblastoma, whether HDACs including HDAC6 are involved in modulating long non-coding RNAs (lncRNAs) to affect glioblastoma malignancy remains obscure. Methods: Integrative 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 iTRAQ-based proteomic analysis were conducted to identify RNA modulators. The effect of LINC00461 on glioblastoma malignancy was evaluated using animal models and cell proliferation-related assays. Functional analysis of the LINC00461 downstream network was performed comprehensively using ingenuity pathway analysis and public databases. Results: We identified a lncRNA, LINC00461, which was substantially increased in TMZ-resistant glioblastoma cells. It was inversely correlated with the survival of mice bearing glioblastoma and was stabilized by interaction between HDAC6 and RNA-binding proteins (RBPs) such as CNOT6 and FUS. Targeting LINC00461 using MPT0B291, an HDAC6 inhibitor, decreased cell division-related proteins via the lncRNA-microRNA (miRNA)-mRNA network and caused cell cycle arrest, thereby suppressing proliferation in parental and TMZ-resistant glioblastoma cells and prolonging the survival of mice bearing glioblastoma. Conclusions: This study sheds light on the role of LINC00461 in glioblastoma malignancy and provides a novel therapeutic strategy for targeting the HDAC6/RBP/LINC00461 axis and its downstream effectors in patients with GBM.

ORGANISM(S): Homo sapiens

PROVIDER: GSE182220 | GEO | 2022/02/08

REPOSITORIES: GEO

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