M6A demethylase fat mass and obesity-associated protein regulates cisplatin resistance of gastric cancer by modulating autophagy activation through ULK1

被引：31
|
作者：
Zhang, Yan [1 ,2 ]
Gao, Ling-xi [2 ]
Wang, Wen [2 ]
Zhang, Teng [2 ]
Dong, Fang-yi [3 ]
Ding, Wen-ping [1 ,4 ]
机构：
[1] Wannan Med Coll, Anhui Higher Educ Inst, Key Lab Noncoding RNA Transformat Res, Wuhu, Peoples R China
[2] Yijishan Hosp, Wannan Med Coll, Affiliated Hosp 1, Dept Gastroenterol, Wuhu, Peoples R China
[3] Shanghai Jiao Tong Univ, Sch Med, Ruijin Hosp, State Key Lab Med Gen,Natl Res Ctr Translat Med, Shanghai 200025, Peoples R China
[4] Yijishan Hosp, Wannan Med Coll, Affiliated Hosp 1, Dept Radiotherapy, Wuhu 241001, Peoples R China
来源：
CANCER SCIENCE | 2022年 / 113卷 / 09期
关键词：
autophagy; cisplatin resistance; FTO; gastric cancer; ULK1; CELL LUNG-CANCER; DRUG-RESISTANCE; APOPTOSIS; INHIBITOR; COMPLEX;
D O I：
10.1111/cas.15469
中图分类号：
R73 [肿瘤学];
学科分类号：
100214 ;
摘要：
Drug resistance is an important factor for treatment failure of gastric cancer. N-6-methyladenosine (m(6)A) is the predominant mRNA internal modification in eukaryotes. The roles of m(6)A modification in drug resistance of gastric cancer remains unclear. In the present study, the m(6)A methylated RNA level was significantly decreased while the expression of m(6)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-m(6)A-dependent and YTHDF2-mediated manner. Collectively, our findings indicate that the FTO/ULK1 axis exerts crucial roles in cisplatin resistance of gastric cancer.
引用
收藏
页码：3085 / 3096
页数：12
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