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ALKBH5 impacts malignancy of hepatocellular carcinoma via m6A-mediated epigenetic modulation

ABSTRACT: N6-methyladenosine (m6A) modification is implicated in the tumorigenicity of hepatocellular carcinoma (HCC). AlkB homolog 5 (ALKBH5) is one of the m6A demethylases, and it has not been well characterized in HCC. In our study we clarify the biological roles and potential mechanisms of ALKBH5 in HCC. We identify the expression profile of ALKBH5 in HCC and find that it serves as an independent prognostic factor of HCC survival. It impacts the proliferation and invasion capability of HCC cells in vitro and in vivo. ALKBH5-mediated m6A demethylation leads to a post-transcriptional modulation of LYPD1. In addition, we reveal the tumor-related behaviors of LYPD1.

ORGANISM(S): Homo sapiens

PROVIDER: GSE149510 | GEO | 2020/08/11

REPOSITORIES: GEO

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The interacted proteins of ALKBH5 and FTO identified by IP-mass

Project description:Since m6A demethylases (FTO and ALKBH5) have been reported to be involved in pre-mRNA splicing regulation, we hypothesized that dynamic m6A distribution during mRNA maturation might involve removal of m6A in internal exons by FTO or ALKBH5 accompanied by splicing factors. To explore this we performed pull-down assays coupled with protein mass spectrometry.

2022-12-09 | PXD038705 | Pride

ALKBH5 is a New Mammalian RNA Demethylase

Project description:N6-methyladenosine (m6A) is the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes. Here we report ALKBH5 as a new mammalian demethylase that oxidatively removes the m6A modification in mRNA in vitro and inside cells. This demethylation activity of ALKBH5 significantly affects mRNA export and RNA metabolism as well as the assembly of mRNA processing factors in nuclear speckles. Alkbh5-deficient male mice are characterized by impaired fertility resulting from apoptosis that affects meiotic metaphase-stage spermatocytes. In accordance with this defect, we have identified in mouse testes 1552 differentially expressed genes which cover broad functional categories and include spermatogenesis-related mRNAs involved in the p53 functional interaction network. We show that Alkbh5-deficiency impacts the expression levels of some of these mRNAs, supporting the observed phenotype. The discovery of this new RNA demethylase strongly suggests that the reversible m6A modification plays fundamental and broad functions in mammalian cells. RNA-seq in two cell types

2013-02-15 | E-GEOD-40132 | biostudies-arrayexpress

The m6A Demethylase ALKBH5 Maintains Tumorigenicity of Glioblastoma Stem-Like Cells by Sustaining FOXM1 Expression and Cell Proliferation Programing

Project description:The dynamic and reversible N6-methyladenosine (m6A) RNA modification installed and erased by N6-methyltransferases and demethylases regulates gene expression and cell fate. Here, we show that the m6A demethylase ALKBH5 is highly expressed in glioblastoma stem-like cells (GSCs). Silencing ALKBH5 suppresses the proliferation of patient-derived GSCs in vitro and in vivo. Integrated transcriptome and m6A-seq analyses revealed altered expression of select ALKBH5 target genes, including FOXM1, a critical transcription factor for the ALKBH5-dependent cell cycle gene expression. ALKBH5 binds to and demethylates FOXM1 nascent transcripts, leading to enhanced FOXM1 expression. Further, a long noncoding RNA antisense to the FOXM1 (FOXM1-AS) interacts with ALKBH5 and FOXM1 nascent transcripts and promotes their interaction. Depleting ALKBH5 and FOXM1-AS disrupted GSC tumorigenesis through the FOXM1 axis. Our work uncovers a novel function for ALKBH5 in maintaining GSC tumorigenicity and provides insight into critical roles of the m6A RNA methylation in human brain tumor.

2017-03-28 | GSE87515 | GEO

ALKBH5 Induces Fibroblast-to-Myofibroblast Transformation During Hypoxia to Protect Against Cardiac Rupture After Myocardial Infarction

Project description:Objectives: To investigate the role of ALKBH5 in fibroblasts during post-myocardial infarction (MI) repair. Background: N6-methyladenosine (m6A) mRNA modification has been shown to play an important role in cardiovascular diseases. The RNA demethylase, AlkB homolog 5 (ALKBH5), is an m6A "eraser" that is responsible for decreased m6A methylation. However, its role in cardiac fibroblasts during the post-MI healing process remains elusive. Methods: MI was mimicked by permanent left anterior descending artery ligation in global ALKBH5-knockout, ALKBH5-knockin, and fibroblast-specific ALKBH5-knockout mice to study the function of ALKBH5 during post-MI collagen repair. Methylated RNA immunoprecipitation sequencing was performed to explore potential ALKBH5 targets. Results: Dramatic alterations in ALKBH5 expression were observed during the early stage post-MI and in hypoxic fibroblasts. Global ALKBH5 knockin reduced infarct size and improved cardiac function after MI. The global and fibroblast-specific ALKBH5-knockout mice both exhibited low survival rates along with poor collagen repair, impaired cardiac function, and cardiac rupture. Both in vivo and in vitro ALKBH5 loss led to impaired fibroblast activation and decreased collagen deposition. Additionally, hypoxia, but not TGF-β1 or Ang II, upregulated ALKBH5 expression in myofibroblasts in a HIF-1α-dependent transcriptional manner. Mechanistically, ALKBH5 promoted the stability of ErbB4 mRNA and the degradation of ST14 mRNA via m6A demethylation. Fibroblast-specific ErbB4 overexpression ameliorated the impaired fibroblast-to-myofibroblast transformation and poor post-MI repair due to ALKBH5 knockout. Conclusions: Fibroblast ALKBH5 positively regulates post-MI healing via post-transcriptional modification and stabilization of ErbB4 mRNA in an m6A-dependent manner. Targeting ALKBH5/ERBB4 may be a potential therapeutic option for post-MI cardiac rupture.

2023-10-01 | GSE226415 | GEO

ALKBH5 impacts malignancy of hepatocellular carcinoma via m6A-mediated epigenetic modulation

Project description:ALKBH5 impacts malignancy of hepatocellular carcinoma via m6A-mediated epigenetic modulation

| PRJNA628947 | ENA

The N6-methyadenosine (m6A) levels in PC9 cell lines.

Project description:ALKBH5 (AlkB homolog 5) has been identified as a eukaryotic demethylase, which catalyzes N6 adenosine. N6-methyladenosine (m6A) is oxidatively demethylated by ALKBH5 with α-ketoglutarate as a substrate and Fe (II) as a coenzyme. We used microarrays to detail the differential gene expression by ALKBH5 knockdown in lung cancer cell lines.

2022-06-01 | GSE165454 | GEO

Expression data from lung cancer cell lines

2022-06-01 | GSE165453 | GEO

ALKBH5 K235 acetylation regulates the RNA m6A profiles

Project description:We performed the transcripome-wild m6A-sequencing to compare the m6A profiles of negative control (NC) HeLa cells and ALKBH5 KO HeLa cells stably re-expressing wild type ALKBH5 (WT) or its mutant K235R (K235R)

2021-06-30 | GSE142203 | GEO

Transcriptome-wide m6A Methylation Profiling of Wild Type and ALKBH5-/- Peritoneal Macrophages by m6A-seq

Project description:By performing m6A-seq analysis on the peritoneal macrophages that derived from ALKBH5-/- mice and littermate mice infected with or without vesicular stomatitis virus (VSV), we want to investigate whether ALKBH5 deficiency-mediated m6A RNA methylation contributes to the regulation of its target genes expression. m6A-seq analysis revealed enriched and specific m6A peaks on the transcript of ALKBH5-targeted gene, which were substantially increased in ALKBH5-deficient peritoneal macrophages than that in wild-type cells whatever infected with or without VSV. Meanwhile we didn’t observe up-regulation of m6A signal on VSV in ALKBH5-deficient cells; and also didn't find significant difference of m6A signals on IFN-β mRNA between ALKBH5-deficient and wild type cells whatever infected with or without VSV. These demonstrated that deficiency of ALKBH5 controls viral replication by increasing the m6A modification of ALKBH5 target gene to regulate its expression.

2019-08-22 | GSE127732 | GEO

RNA demethylase ALKBH5 promotes tumorigenesis in multiple myeloma [m6A-seq]

Project description:We here report ALKBH5, a m6A RNA demethylase, as a crucial oncogene in multiple myeloma (MM). Using various MM models, we demonstrated a critical requirement of ALKBH5 for MM cell proliferation in vitro and in vivo. To identify the potential mRNA targets of ALKBH5, we conducted m6A-seq with mRNA samples enriched from MM cells with or without ALKBH5 knockdown.

2022-07-07 | GSE180207 | GEO

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