Essential role of ALKBH5-mediated RNA demethylation modification in bile acid-induced gastric intestinal metaplasia
In: Molecular Therapy - Nucleic Acids, Jg. 26 (2021-12-01), S. 458-472
Online
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Zugriff:
Bile acid reflux and subsequent caudal-related homeobox 2 (CDX2) activation contribute to gastric intestinal metaplasia (IM), a precursor of gastric cancer; however, the mechanism underlying this phenomenon is unclear. Here, we demonstrate that alkylation repair homolog protein 5 (ALKBH5), a major RNA N6-adenosine demethylase, is required for bile acid-induced gastric IM. Mechanistically, we revealed the N6-methyladenosine (m6A) modification profile in gastric IM for the first time and identified ZNF333 as a novel m6A target of ALKBH5. ALKBH5 was shown to demethylate ZNF333 mRNA, leading to enhanced ZNF333 expression by abolishing m6A-YTHDF2-dependent mRNA degradation. In addition, ALKBH5 activated CDX2 and downstream intestinal markers by targeting the ZNF333/CYLD axis and activating NF-κB signaling. Reciprocally, p65, the key transcription factor of the canonical NF-κB pathway, enhanced the transcription activity of ALKBH5 in the nucleus, thus forming a positive feedforward circuit. Furthermore, ALKBH5 levels were positively correlated with ZNF333 and CDX2 levels in IM tissues, indicating significant clinical relevance. Collectively, our findings suggest that an m6A modification-associated positive feedforward loop between ALKBH5 and NF-κB signaling is involved in generating the IM phenotype of gastric epithelial cells. Targeting the ALKBH5/ZNF333/CYLD/CDX2 axis may be a useful therapeutic strategy for gastric IM in patients with bile regurgitation.
Graphical abstract
We revealed the N6-methyladenosine modification profile in gastric intestinal metaplasia development for the first time. Targeting the ALKBH5/ZNF333/CYLD/CDX2 axis may be a useful preventive and therapeutic strategy for gastric intestinal metaplasia in patients with bile regurgitation and therefore may have great value for clinical transformation.
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Essential role of ALKBH5-mediated RNA demethylation modification in bile acid-induced gastric intestinal metaplasia
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Autor/in / Beteiligte Person: | Yue, Ben ; Wang, Ming ; Cui, Ran ; Zheng, Ruizhe ; Jin, Weilin ; Yu, Fengrong ; Zhao, Enhao ; Song, Chenlong ; Bao, Tianshang |
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Zeitschrift: | Molecular Therapy - Nucleic Acids, Jg. 26 (2021-12-01), S. 458-472 |
Veröffentlichung: | Elsevier BV, 2021 |
Medientyp: | unknown |
ISSN: | 2162-2531 (print) |
DOI: | 10.1016/j.omtn.2021.08.019 |
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