N6-methyladenosine demethylase FTO promotes growth and metastasis of gastric cancer via m6A modification of caveolin-1 and metabolic regulation of mitochondrial dynamics

You Zhou,Bin Xu,Yingting Liu,Yufang Shi,Haifeng Deng,Yi Zhou,Qi Wang,Xiao Zheng,Jingting Jiang,Jian Liu

doi:10.1038/s41419-022-04503-7

You Zhou, Bin Xu + Show 8 more

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https://doi.org/10.1038/s41419-022-04503-7

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Abstract

Gastric cancer (GC) is the fifth most common tumor and the third most deadly cancer worldwide. N6-methyladenosine (m6A) modification has been reported to play a regulatory role in human cancers. However, the exact role of m6A in GC remains largely unknown, and the dysregulation of m6A on mitochondrial metabolism has never been studied. In the present study, we demonstrated that FTO, a key demethylase for RNA m6A modification, was up-regulated in GC tissues, especially in tissues with liver metastasis. Functionally, FTO acted as a promoter for the proliferation and metastasis in GC. Moreover, FTO enhanced the degradation of caveolin-1 mRNA via its demethylation, which regulated the mitochondrial fission/fusion and metabolism. Collectively, our current findings provided some valuable insights into FTO-mediated m6A demethylation modification and could be used as a new strategy for more careful surveillance and aggressive therapeutic intervention.

Highlights

Gastric cancer (GC) is the fifth most common tumor and the third most deadly cancer worldwide, with almost half of global GC cases diagnosed in East Asia [1]
fat mass and obesity-associated protein (FTO) expression is up-regulated in GC tissues and its prognostic value in GC To explore the expression profile of the major m6A eraser enzyme in GC, we first searched the clinical database GEPIA and found that the expression of FTO at the mRNA level in GC tissues was significantly higher compared with the normal tissues (Fig. 1A)
We examined the expression of FTO at the protein level in the GC tissue using a microarray consisting of 90 cases by IHC

Summary

Introduction

Gastric cancer (GC) is the fifth most common tumor and the third most deadly cancer worldwide, with almost half of global GC cases diagnosed in East Asia [1]. Most GC patients are first diagnosed in the late stage of malignant hyperplasia and metastasis [2]. Cancer cells support the occurrence and development of malignant tumors through metabolic recombination, especially mitochondrial metabolism [5]. Glycolysis has long been considered as the main metabolic process for energy production and anabolic growth of cancer cells [6]. Such insights are instrumental in the development of powerful imaging tools that are still used in clinics, it is clear that mitochondria play a key role in tumorigenesis [7]. It is critical to understand the molecular mechanisms of mitochondrial metabolism in GC in order to develop future diagnostic and therapeutic strategies

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