M6 A demethylase fat mass and obesity-associated protein regulates cisplatin resistance of gastric cancer by modulating autophagy activation through ULK1.

Abstract

Drug resistance is an important factor for treatment failure of gastric cancer. N6 -methyladenosine (m6 A) is the predominant mRNA internal modification in eukaryotes. The roles of m6 A modification in drug resistance of gastric cancer remains unclear. In the present study, the m6 A methylated RNA level was significantly decreased while the expression of m6 A demethylase fat mass and obesity-associated protein (FTO) was obviously elevated in cisplatin-resistant (SGC-7901/DDP) gastric cancer cells. Knockdown of FTO reversed cisplatin resistance of SGC-7901/DDP cells both in vitro and in vivo, which was attributed to the inhibition of Unc-51-like kinase 1 (ULK1)-mediated autophagy. Mechanistically, ULK1 expression was regulated in an FTO-m6 A-dependent and YTHDF2-mediated manner. Collectively, our findings indicate that the FTO/ULK1 axis exerts crucial roles in cisplatin resistance of gastric cancer.

• Authors: Yan Zhang, Ling-Xi Gao, Wen Wang, Teng Zhang, Fang-Yi Dong, Wen-Ping Ding
• Journal: Cancer science (Cancer Sci) Vol. 113 Issue 9 Pg. 3085-3096 (Sep 2022) ISSN: 1349-7006 [Electronic] England
• PMID: 35730319 (Publication Type: Journal Article)
• Copyright: © 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.

Chemical References

• Intracellular Signaling Peptides and Proteins
• Alpha-Ketoglutarate-Dependent Dioxygenase FTO
• FTO protein, human
• Autophagy-Related Protein-1 Homolog
• ULK1 protein, human
• Cisplatin

Topics

• Alpha-Ketoglutarate-Dependent Dioxygenase FTO (genetics, metabolism)
• Apoptosis
• Autophagy (genetics)
• Autophagy-Related Protein-1 Homolog (genetics)
• Cisplatin (pharmacology, therapeutic use)
• Humans
• Intracellular Signaling Peptides and Proteins (genetics, therapeutic use)
• Obesity (genetics)
• Stomach Neoplasms (drug therapy, genetics)