DNA 6mA demethylase ALKBH1 regulates DDX18 expression to promote proliferation of human head and neck squamous cell carcinoma

Guo, Chi; Liu, Zheming; Zhang, Haojian

doi:10.1007/s13402-023-00800-1

Cited by 6 publications

(4 citation statements)

References 38 publications

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“…N6AMT1, identified as the methyltransferase responsible for nuclear 6mA methylation, might potentially shape 6mA DNA patterns through an indirect mechanism ( Figure 2 ) ( 55 ). Additionally, Jumu and SSBP1 are categorized as 6mA-DNA-binding factors and are considered “readers” ( 56 , 57 ). Studies have shown that a decrease in N6AMT1 is correlated with reduced DNA 6mA levels, increased tumor progression, and an unfavorable prognosis for breast cancer (BC) patients.…”

Section: Ma Methylation In Autophagy Regulationmentioning

confidence: 99%

Epigenetic targeting of autophagy for cancer: DNA and RNA methylation

Lin,

Zhao,

Zheng

et al. 2023

Front. Oncol.

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Autophagy, a crucial cellular mechanism responsible for degradation and recycling of intracellular components, is modulated by an intricate network of molecular signals. Its paradoxical involvement in oncogenesis, acting as both a tumor suppressor and promoter, has been underscored in recent studies. Central to this regulatory network are the epigenetic modifications of DNA and RNA methylation, notably the presence of N6-methyldeoxyadenosine (6mA) in genomic DNA and N6-methyladenosine (m6A) in eukaryotic mRNA. The 6mA modification in genomic DNA adds an extra dimension of epigenetic regulation, potentially impacting the transcriptional dynamics of genes linked to autophagy and, especially, cancer. Conversely, m6A modification, governed by methyltransferases and demethylases, influences mRNA stability, processing, and translation, affecting genes central to autophagic pathways. As we delve deeper into the complexities of autophagy regulation, the importance of these methylation modifications grows more evident. The interplay of 6mA, m6A, and autophagy points to a layered regulatory mechanism, illuminating cellular reactions to a range of conditions. This review delves into the nexus between DNA 6mA and RNA m6A methylation and their influence on autophagy in cancer contexts. By closely examining these epigenetic markers, we underscore their promise as therapeutic avenues, suggesting novel approaches for cancer intervention through autophagy modulation.

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Section: Ma Methylation In Autophagy Regulationmentioning

confidence: 99%

Epigenetic targeting of autophagy for cancer: DNA and RNA methylation

Lin,

Zhao,

Zheng

et al. 2023

Front. Oncol.

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“…25,26 ALKBH1 is shown to be able to erase 6mA in vitro and in patient-derived human glioblastoma models, 18,27 cells, 28 and human cancer cell lines. 29 A very recent study by Li et al revealed that ALKBH1 functions as a nuclear eraser of 6mA in unpairing regions of mammalian genomes and prefers bubbled or bulged DNAs as substrate, instead of singlestranded (ss-) or double-stranded (ds-) DNAs. 30,31 They also revealed the substrate preference mechanism of ALKBH1 by structural biology techniques.…”

Section: ■ Introductionmentioning

confidence: 99%

“…ALKBH1 belongs to the Fe(II) and α-ketoglutarate (α-KG)-dependent dioxygenase AlkB family, , which also comprises two well-known RNA m6A demethylases, fat mass and obesity-associated protein (FTO) and ALKBH5. , ALKBH1 is shown to be able to erase 6mA in vitro and in patient-derived human glioblastoma models, , human mesenchymal stem cells, and human cancer cell lines . A very recent study by Li et al revealed that ALKBH1 functions as a nuclear eraser of 6mA in unpairing regions of mammalian genomes and prefers bubbled or bulged DNAs as substrate, instead of single-stranded (ss-) or double-stranded (ds-) DNAs. , They also revealed the substrate preference mechanism of ALKBH1 by structural biology techniques.…”

Section: Introductionmentioning

confidence: 99%

Discovery of a Potent and Cell-Active Inhibitor of DNA 6mA Demethylase ALKBH1

Xiong,

Li,

Guo

et al. 2024

J. Am. Chem. Soc.

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N 6-Methyladenine (6mA) of DNA has emerged as a novel epigenetic mark in eukaryotes, and several 6mA effector proteins have been identified. However, efforts to selectively inhibit the biological functions of these effector proteins with small molecules are unsuccessful to date. Here we report the first potent and selective small molecule inhibitor (13h) of AlkB homologue 1 (ALKBH1), the only validated 6mA demethylase. 13h showed an IC50 of 0.026 ± 0.013 μM and 1.39 ± 0.13 μM in the fluorescence polarization (FP) and enzyme activity assay, respectively, and a K D of 0.112 ± 0.017 μM in the isothermal titration calorimetry (ITC) assay. The potency of 13h was well explained by the cocrystal structure of the 13h-ALKBH1 complex. Furthermore, 13h displayed excellent selectivity for ALKBH1. In cells, compound 13h and its derivative 16 were able to engage ALKBH1 and modulate the 6mA levels. Collectively, our study identified the first potent, isoform selective, and cell-active ALKBH1 inhibitor, providing a tool compound for exploring the biological functions of ALKBH1 and DNA 6mA.

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“…Mechanistically, they found that ALKBH1 activates bone morphogenetic protein 2( BMP2 ) and aggravates osteogenic reprogramming in chronic kidney disease 20 . A recent study revealed that ALKBH1 is highly expressed in human head and neck squamous cell carcinoma cells and patient tissues, promoting cell proliferation by enhancing DDX18 expression 21 . More importantly, Rashad, S. et al uncovered that ALKBH1 assists tRNA cleavage in demethylation stress in rat neuroblastoma cells 22 .…”

Section: Introductionmentioning

confidence: 99%

ALKBH1 rs2267755 C>T polymorphism decreases neuroblastoma risk in Chinese children

Zhang,

Zhou,

Zhao

et al. 2024

J. Cancer

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Neuroblastoma is a highly malignant extracranial solid tumor in pediatrics. ALKBH1 as a recently discovered DNA N6-methyldeoxyadenosine (6mA) demethylase closely links to tumorigenesis. Whether the ALKBH1 polymorphism contributes to neuroblastoma risk remains unclear. In the present study, we genotyped the ALKBH1 single nucleotide polymorphisms (SNPs) in 402 neuroblastoma patients and 473 healthy controls by TaqMan assay. Odds ratios (ORs) and 95% confidence intervals (CIs) were also calculated to evaluate the strength of the association. Our result exhibited that the rs2267755 C>T (CT vs. CC, adjusted OR=0.69, 95% CI=0.50-0.94, P =0.019) is significantly associated with reduced neuroblastoma risk. And its protective effect is particularly significant in children with tumors originating from the retroperitoneal. Combined genotype analysis revealed that carriers with 1-2 protective genotypes are more susceptible to neuroblastoma than those with 3-4 protective genotypes (adjusted OR=0.71, 95% CI=0.53-0.97, P =0.028). Moreover, the rs2267755 C>T is significantly associated with messenger RNA (mRNA) expression of ALKBH1 and three of its surrounding genes, including SNWQ, ADCK1 , and RPL21P10 . These results suggest that the rs2267755 C>T may be a genetic variant to reduce neuroblastoma risk.

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DNA 6mA demethylase ALKBH1 regulates DDX18 expression to promote proliferation of human head and neck squamous cell carcinoma

Cited by 6 publications

References 38 publications

Epigenetic targeting of autophagy for cancer: DNA and RNA methylation

Epigenetic targeting of autophagy for cancer: DNA and RNA methylation

Discovery of a Potent and Cell-Active Inhibitor of DNA 6mA Demethylase ALKBH1

ALKBH1 rs2267755 C>T polymorphism decreases neuroblastoma risk in Chinese children

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