Essential role of ALKBH5-mediated RNA demethylation modification in bile acid-induced gastric intestinal metaplasia

Ben Yue; Ran Cui; Ruizhe Zheng; Weilin Jin; Chenlong Song; Tianshang Bao; Ming Wang; Fengrong Yu; Enhao Zhao

doi:10.1016/j.omtn.2021.08.019

Essential role of ALKBH5-mediated RNA demethylation modification in bile acid-induced gastric intestinal metaplasia

Mol Ther Nucleic Acids. 2021 Aug 26:26:458-472. doi: 10.1016/j.omtn.2021.08.019. eCollection 2021 Dec 3.

Authors

Ben Yue¹, Ran Cui², Ruizhe Zheng³, Weilin Jin⁴, Chenlong Song⁵, Tianshang Bao¹, Ming Wang¹, Fengrong Yu¹, Enhao Zhao¹

Affiliations

¹ Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai 200127, China.
² Department of Hepatopancreatobiliary Surgery, Shanghai East Hospital, Tongji University School of Medicine, 1800 Yuntai Road, Shanghai 200120, China.
³ Department of Neurosurgery, Tongren Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200336, China.
⁴ Institute of Cancer Neuroscience, Medical Frontier Innovation Research Center, The First Hospital of Lanzhou University, The First Clinical Medical College of Lanzhou University, Lanzhou 730000, China.
⁵ Department of General Surgery, Shanghai General Hospital, School of Medicine, Shanghai Jiao Tong University, 85 Wujin Road, Shanghai 200080, China.

Abstract

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.

Keywords: ALKBH5; IM; NF-κB signaling; ZNF333; m6A.