LINC00659 cooperated with ALKBH5 to accelerate gastric cancer progression by stabilising JAK1 mRNA in an m6A‐YTHDF2‐dependent manner

Abstract Background N6‐methyladenosine (m6A) RNA modification is known as a common epigenetic regulation form in eukaryotic cells. Emerging studies show that m6A in noncoding RNAs makes a difference, and the aberrant expression of m6A‐associated enzymes may cause diseases. The demethylase alkB homologue 5 (ALKBH5) plays diverse roles in different cancers, but its role during gastric cancer (GC) progression is not well known. Methods The quantitative real‐time polymerase chain reaction, immunohistochemistry staining and western blotting assays were used to detect ALKBH5 expression in GC tissues and human GC cell lines. The function assays in vitro and xenograft mouse model in vivo were used to investigate the effects of ALKBH5 during GC progression. RNA sequencing, MeRIP sequencing, RNA stability and luciferase reporter assays were performed to explore the potential molecular mechanisms involved in the function of ALKBH5. RNA binding protein immunoprecipitation sequencing (RIP‐seq), RIP and RNA pull‐down assays were performed to examine the influence of LINC00659 on the ALKBH5–JAK1 interaction. Results ALKBH5 was highly expressed in GC samples and associated with aggressive clinical features and poor prognosis. ALKBH5 promoted the abilities of GC cell proliferation and metastasis in vitro and in vivo. The m6A modification on JAK1 mRNA was removed by ALKBH5, which resulted in the upregulated expression of JAK1. LINC00659 facilitated ALKBH5 binding to and upregulated JAK1 mRNA depending on an m6A‐YTHDF2 manner. Silencing of ALKBH5 or LINC00659 disrupted GC tumourigenesis via the JAK1 axis. JAK1 upregulation activated the JAK1/STAT3 pathway in GC. Conclusion ALKBH5 promoted GC development via upregulated JAK1 mRNA expression mediated by LINC00659 in an m6A‐YTHDF2‐dependent manner, and targeting ALKBH5 may be a promising therapeutic method for GC patients.

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