HDAC6 involves in regulating the lncRNA-microRNA-mRNA network to promote the proliferation of glioblastoma cells

An Chih Wu, Wen Bin Yang, Kwang Yu Chang, Jung Shun Lee, Jing Ping Liou, Ruei Yuan Su, Siao Muk Cheng, Daw Yang Hwang, Ushio Kikkawa, Tsung I. Hsu, Chih Yang Wang, Wen Chang Chang, Pin Yuan Chen, Jian Ying Chuang

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Glioblastoma (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. 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 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. Results: We 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. Conclusions: This 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.

Original languageEnglish
Article number47
JournalJournal of Experimental and Clinical Cancer Research
Volume41
Issue number1
DOIs
Publication statusPublished - Dec 2022

Keywords

  • Glioblastoma
  • Histone deacetylase 6
  • lncRNA LINC00461
  • RNA-binding proteins

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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