2. Academic Validation
  3. HDAC6 involves in regulating the lncRNA-microRNA-mRNA network to promote the proliferation of glioblastoma cells

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

  • J Exp Clin Cancer Res. 2022 Feb 2;41(1):47. doi: 10.1186/s13046-022-02257-w.
An-Chih Wu 1,  Wen-Bin Yang  # 1 2 3,  Kwang-Yu Chang  # 4,  Jung-Shun Lee  # 5,  Jing-Ping Liou  # 6,  Ruei-Yuan Su 1,  Siao Muk Cheng 4,  Daw-Yang Hwang 4,  Ushio Kikkawa 1,  Tsung-I Hsu 2 3 7 8,  Chih-Yang Wang 9,  Wen-Chang Chang 1,  Pin-Yuan Chen 10,  Jian-Ying Chuang 11 12 13 14 15
Affiliations

Affiliations

  • 1 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.
  • 2 The Ph.D. Program for Neural Regenerative Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan.
  • 3 TMU Research Center of Neuroscience, Taipei Medical University, Taipei, Taiwan.
  • 4 National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan.
  • 5 Department of Neurosurgery, National Cheng Kung University Hospital, Tainan, Taiwan.
  • 6 School of Pharmacy, Taipei Medical University, Taipei, Taiwan.
  • 7 TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan.
  • 8 Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
  • 9 The Ph.D. Program for Cancer Molecular Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan.
  • 10 Department of Neurosurgery, Keelung Chang Gung Memorial Hospital, Chang Gung University, 222 Mai-jin Road, Keelung, 20401, Taiwan. pinyuanc@cgmh.org.tw.
  • 11 The Ph.D. Program for Neural Regenerative Medicine, Taipei Medical University, 250 Wuxing Street, Taipei, 11031, Taiwan. chuangcy@tmu.edu.tw.
  • 12 TMU Research Center of Neuroscience, Taipei Medical University, Taipei, Taiwan. chuangcy@tmu.edu.tw.
  • 13 TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan. chuangcy@tmu.edu.tw.
  • 14 Cell Physiology and Molecular Image Research Center, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. chuangcy@tmu.edu.tw.
  • 15 Department of Biomedical Science and Environmental Biology, Kaohsiung Medical University, Kaohsiung, Taiwan. chuangcy@tmu.edu.tw.
  • # Contributed equally.
PMID: 35109908 DOI: 10.1186/s13046-022-02257-w
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.

Keywords

Glioblastoma; Histone deacetylase 6; RNA-binding proteins; lncRNA LINC00461.

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