Browse
Submit Data
Databases
API
Help

Dataset Information

17 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

RNA demethylase ALKBH5 in cancer: from mechanisms to therapeutic potential.

ABSTRACT: RNA demethylase ALKBH5 takes part in the modulation of N⁶-methyladenosine (m⁶A) modification and controls various cell processes. ALKBH5-mediated m⁶A demethylation regulates gene expression by affecting multiple events in RNA metabolism, e.g., pre-mRNA processing, mRNA decay and translation. Mounting evidence shows that ALKBH5 plays critical roles in a variety of human malignancies, mostly via post-transcriptional regulation of oncogenes or tumor suppressors in an m⁶A-dependent manner. Meanwhile, increasing non-coding RNAs are recognized as functional targets of ALKBH5 in cancers. Here we reviewed up-to-date findings about the pathological roles of ALKBH5 in cancer, the molecular mechanisms by which it exerts its functions, as well as the underlying mechanism of its dysregulation. We also discussed the therapeutic implications of targeting ALKBH5 in cancer and potential ALKBH5-targeting strategies.

SUBMITTER: Qu J

PROVIDER: S-EPMC8780705 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

The role of the ALKBH5 RNA demethylase in invasive breast cancer.

Project description:BackgroundN6-methyladenosine (m6A) is the most common internal RNA modification and is involved in regulation of RNA and protein expression. AlkB family member 5 (ALKBH5) is a m6A demethylase. Given the important role of m6A in biological mechanisms, m6A and its regulators, have been implicated in many disease processes, including cancer. However, the contribution of ALKBH5 to invasive breast cancer (BC) remains poorly understood. The aim of this study was to evaluate the clinicopathological value of ALKBH5 in BC.MethodsPublicly available data were used to investigate ALKBH5 mRNA alterations, prognostic significance, and association with clinical parameters at the genomic and transcriptomic level. Differentially expressed genes (DEGs) and enriched pathways with low or high ALKBH5 expression were investigated. Immunohistochemistry (IHC) was used to assess ALKBH5 protein expression in a large well-characterised BC series (n = 1327) to determine the clinical significance and association of ALKBH5 expression.ResultsReduced ALKBH5 mRNA expression was significantly associated with poor prognosis and unfavourable clinical parameters. ALKBH5 gene harboured few mutations and/or copy number alternations, but low ALKBH5 mRNA expression was seen. Patients with low ALKBH5 mRNA expression had a number of differentially expressed genes and enriched pathways, including the cytokine-cytokine receptor interaction pathway. Low ALKBH5 protein expression was significantly associated with unfavourable clinical parameters associated with tumour progression including larger tumour size and worse Nottingham Prognostic Index group.ConclusionThis study implicates ALKBH5 in BC and highlights the need for further functional studies to decipher the role of ALKBH5 and RNA m6A methylation in BC progression.

| S-EPMC11317455 | biostudies-literature

Crystal structure of the RNA demethylase ALKBH5 from zebrafish.

Project description:ALKBH5, a member of AlkB family proteins, has been reported as a mammalian N(6)-methyladenosine (m(6)A) RNA demethylase. Here we report the crystal structure of zebrafish ALKBH5 (fALKBH5) with the resolution of 1.65Å. Structural superimposition shows that fALKBH5 is comprised of a conserved jelly-roll motif. However, it possesses a loop that interferes potential binding of a duplex nucleic acid substrate, suggesting an important role in substrate selection. In addition, several active site residues are different between the two known m(6)A RNA demethylases, ALKBH5 and FTO, which may result in their slightly different pathways of m(6)A demethylation.

| S-EPMC3982313 | biostudies-literature

The DEAD-Box RNA Helicase DDX3 Interacts with m6A RNA Demethylase ALKBH5.

Project description:DDX3 is a member of the family of DEAD-box RNA helicases. DDX3 is a multifaceted helicase and plays essential roles in key biological processes such as cell cycle, stress response, apoptosis, and RNA metabolism. In this study, we found that DDX3 interacted with ALKBH5, an m6A RNA demethylase. The ATP domain of DDX3 and DSBH domain of ALKBH5 were indispensable to their interaction with each other. Furthermore, DDX3 could modulate the demethylation of mRNAs. We also showed that DDX3 regulated the methylation status of microRNAs and there was an interaction between DDX3 and AGO2. The dynamics of m6A RNA modification is still a field demanding further investigation, and here, we add a link by showing that RNA demethylation can be regulated by proteins such as DDX3.

| S-EPMC5733242 | biostudies-literature

Promoting axon regeneration by inhibiting RNA N6-methyladenosine demethylase ALKBH5.

Project description:A key limiting factor of successful axon regeneration is the intrinsic regenerative ability in both the peripheral nervous system (PNS) and central nervous system (CNS). Previous studies have identified intrinsic regenerative ability regulators that act on gene expression in injured neurons. However, it is less known whether RNA modifications play a role in this process. Here, we systematically screened the functions of all common m6A modification-related enzymes in axon regeneration and report ALKBH5, an evolutionarily conserved RNA m6A demethylase, as a regulator of axonal regeneration in rodents. In PNS, knockdown of ALKBH5 enhanced sensory axonal regeneration, whereas overexpressing ALKBH5 impaired axonal regeneration in an m6A-dependent manner. Mechanistically, ALKBH5 increased the stability of Lpin2 mRNA and thus limited regenerative growth associated lipid metabolism in dorsal root ganglion neurons. Moreover, in CNS, knockdown of ALKBH5 enhanced the survival and axonal regeneration of retinal ganglion cells after optic nerve injury. Together, our results suggest a novel mechanism regulating axon regeneration and point ALKBH5 as a potential target for promoting axon regeneration in both PNS and CNS.

| S-EPMC10400074 | biostudies-literature

ALKBH5 is a mammalian RNA demethylase that impacts RNA metabolism and mouse fertility.

Project description:N(6)-methyladenosine (m(6)A) is the most prevalent internal modification of messenger RNA (mRNA) in higher eukaryotes. Here we report ALKBH5 as another mammalian demethylase that oxidatively reverses m(6)A in mRNA in vitro and in vivo. 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 have increased m(6)A in mRNA and 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 1,551 differentially expressed genes that cover broad functional categories and include spermatogenesis-related mRNAs involved in the p53 functional interaction network. The discovery of this RNA demethylase strongly suggests that the reversible m(6)A modification has fundamental and broad functions in mammalian cells.

| S-EPMC3646334 | biostudies-literature

Crystallization and preliminary X-ray diffraction of the RNA demethylase ALKBH5.

Project description:N(6)-methyladenosine (m6A) is a ubiquitous modification found in mammalian mRNA and long noncoding RNA. ALKBH5 is a member of the iron(II)- and 2-oxoglutarate-dependent AlkB oxygenase family and has been shown to catalyze the oxidative demethylation of N(6)-methyladenosine in RNA. The ALKBH5 protein was purified and crystallized using the hanging-drop vapour-diffusion method. The crystals diffracted to 2.4 Å resolution using synchrotron radiation. The crystals belonged to space group P2(1)2(1)2(1), with unit-cell parameters a = 57.456, b = 83.406, c = 92.909 Å, α = β = γ = 90.00° and one molecule in the asymmetric unit.

| S-EPMC3818040 | biostudies-literature

A covalent compound selectively inhibits RNA demethylase ALKBH5 rather than FTO.

Project description:N 6-Methyladenosine (m6A) is the most prevalent mRNA modification and is required for gene regulation in eukaryotes. ALKBH5, an m6A demethylase, is a promising target, particularly for anticancer drug discovery. However, the development of selective and potent inhibitors of ALKBH5 rather than FTO remains challenging. Herein, we used a targeted covalent inhibition strategy and identified a covalent inhibitor, TD19, which selectively inhibits ALKBH5 compared with FTO demethylase in protein-based and tumor cell-based assays. TD19 irreversibly modifies the residues C100 and C267, preventing ALKBH5 from binding to m6A-containing RNA. Moreover, TD19 displays good anticancer efficacy in acute myeloid leukemia and glioblastoma multiforme cell lines. Thus, the ALKBH5 inhibitor developed in this study, which selectively targets ALKBH5 compared with FTO, can potentially be used as a probe for investigating the biological functions of RNA demethylase and as a lead compound in anticancer research.

| S-EPMC10989504 | biostudies-literature

Structure of human RNA N⁶-methyladenine demethylase ALKBH5 provides insights into its mechanisms of nucleic acid recognition and demethylation.

Project description:ALKBH5 is a 2-oxoglutarate (2OG) and ferrous iron-dependent nucleic acid oxygenase (NAOX) that catalyzes the demethylation of N(6)-methyladenine in RNA. ALKBH5 is upregulated under hypoxia and plays a role in spermatogenesis. We describe a crystal structure of human ALKBH5 (residues 66-292) to 2.0 Å resolution. ALKBH5₆₆₋₂₉₂ has a double-stranded β-helix core fold as observed in other 2OG and iron-dependent oxygenase family members. The active site metal is octahedrally coordinated by an HXD…H motif (comprising residues His204, Asp206 and His266) and three water molecules. ALKBH5 shares a nucleotide recognition lid and conserved active site residues with other NAOXs. A large loop (βIV-V) in ALKBH5 occupies a similar region as the L1 loop of the fat mass and obesity-associated protein that is proposed to confer single-stranded RNA selectivity. Unexpectedly, a small molecule inhibitor, IOX3, was observed covalently attached to the side chain of Cys200 located outside of the active site. Modelling substrate into the active site based on other NAOX-nucleic acid complexes reveals conserved residues important for recognition and demethylation mechanisms. The structural insights will aid in the development of inhibitors selective for NAOXs, for use as functional probes and for therapeutic benefit.

| S-EPMC3985658 | biostudies-literature

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

RNA Demethylase ALKBH5 Selectively Promotes Tumorigenesis and Cancer Stem Cell Self-Renewal in Acute Myeloid Leukemia.

Project description:N6-methyladenosine (m6A), the most abundant internal modification in mRNA, has been implicated in tumorigenesis. As an m6A demethylase, ALKBH5 has been shown to promote the development of breast cancer and brain tumors. However, in acute myeloid leukemia (AML), ALKBH5 was reported to be frequently deleted, implying a tumor-suppressor role. Here, we show that ALKBH5 deletion is rare in human AML; instead, ALKBH5 is aberrantly overexpressed in AML. Moreover, its increased expression correlates with poor prognosis in AML patients. We demonstrate that ALKBH5 is required for the development and maintenance of AML and self-renewal of leukemia stem/initiating cells (LSCs/LICs) but not essential for normal hematopoiesis. Mechanistically, ALKBH5 exerts tumor-promoting effects in AML by post-transcriptional regulation of its critical targets such as TACC3, a prognosis-associated oncogene in various cancers. Collectively, our findings reveal crucial functions of ALKBH5 in leukemogenesis and LSC/LIC self-renewal/maintenance and highlight the therapeutic potential of targeting the ALKBH5/m6A axis.

| S-EPMC7335338 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data