METTL3 confers oxaliplatin resistance through the activation of G6PD-enhanced pentose phosphate pathway in hepatocellular carcinoma

奥沙利铂 肝细胞癌 磷酸戊糖途径 癌症研究 化学 医学 内科学 生物化学 新陈代谢 癌症 糖酵解 结直肠癌
作者
Xiaohan Jin,Yong-rui Lv,Fengjie Bie,Jin‐Ling Duan,Chao Ma,Miaomiao Dai,Jiewei Chen,Lianghe Lu,Shui-Dan Xu,Jie Zhou,Si Li,Jiong Bi,Fengwei Wang,Dan Xie,Muyan Cai
出处
期刊:Cell Death & Differentiation [Springer Nature]
标识
DOI:10.1038/s41418-024-01406-2
摘要

Abstract Oxaliplatin-based therapeutics is a widely used treatment approach for hepatocellular carcinoma (HCC) patients; however, drug resistance poses a significant clinical challenge. Epigenetic modifications have been implicated in the development of drug resistance. In our study, employing siRNA library screening, we identified that silencing the m 6 A writer METTL3 significantly enhanced the sensitivity to oxaliplatin in both in vivo and in vitro HCC models. Further investigations through combined RNA-seq and non-targeted metabolomics analysis revealed that silencing METTL3 impeded the pentose phosphate pathway (PPP), leading to a reduction in NADPH and nucleotide precursors. This disruption induced DNA damage, decreased DNA synthesis, and ultimately resulted in cell cycle arrest. Mechanistically, METTL3 was found to modify E3 ligase TRIM21 near the 3’UTR with N 6 -methyladenosine, leading to reduced RNA stability upon recognition by YTHDF2. TRIM21, in turn, facilitated the degradation of the rate-limiting enzyme of PPP, G6PD, through the ubiquitination-proteasome pathway. Importantly, high expression of METTL3 was significantly associated with adverse prognosis and oxaliplatin resistance in HCC patients. Notably, treatment with the specific METTL3 inhibitor, STM2457, significantly improved the efficacy of oxaliplatin. These findings underscore the critical role of the METTL3/TRIM21/G6PD axis in driving oxaliplatin resistance and present a promising strategy to overcome chemoresistance in HCC.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
更新
大幅提高文件上传限制,最高150M (2024-4-1)

科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
乐正一兰完成签到,获得积分10
刚刚
lk65734完成签到,获得积分10
刚刚
Fei发布了新的文献求助10
刚刚
学学完成签到,获得积分10
1秒前
1秒前
认真书竹发布了新的文献求助10
1秒前
Oreki完成签到,获得积分10
1秒前
大王869完成签到 ,获得积分10
2秒前
无花果应助ablexm采纳,获得10
2秒前
汉堡包应助孤独的小蜜蜂采纳,获得10
3秒前
天道酬勤发布了新的文献求助10
3秒前
3秒前
隐形人发布了新的文献求助10
4秒前
脆瓜完成签到,获得积分10
4秒前
丘比特应助sc采纳,获得10
5秒前
张靖超完成签到 ,获得积分10
5秒前
天天快乐应助H-kevin.采纳,获得10
6秒前
6秒前
yihoxu发布了新的文献求助10
8秒前
佳雪儿完成签到,获得积分10
8秒前
花开米兰城完成签到,获得积分10
9秒前
小牙医完成签到,获得积分10
9秒前
弹指一挥间完成签到,获得积分10
9秒前
stuffmatter举报求助违规成功
9秒前
个性归尘举报求助违规成功
9秒前
宁少爷举报求助违规成功
9秒前
9秒前
shi完成签到,获得积分20
10秒前
冰儿菲菲完成签到,获得积分10
11秒前
ysy完成签到,获得积分10
12秒前
yihoxu完成签到,获得积分20
12秒前
naive完成签到,获得积分10
12秒前
Owen应助Tammy采纳,获得10
12秒前
周周完成签到 ,获得积分10
12秒前
矛尾复虾虎鱼完成签到,获得积分10
13秒前
13秒前
111完成签到,获得积分10
13秒前
LVVVB发布了新的文献求助10
13秒前
13秒前
STAN完成签到,获得积分10
14秒前
高分求助中
Sustainability in Tides Chemistry 2000
Microlepidoptera Palaearctica, Volumes 1 and 3 - 13 (12-Volume Set) [German] 1122
Дружба 友好报 (1957-1958) 1000
The Data Economy: Tools and Applications 1000
Mantiden - Faszinierende Lauerjäger – Buch gebraucht kaufen 700
PraxisRatgeber Mantiden., faszinierende Lauerjäger. – Buch gebraucht kaufe 700
A Dissection Guide & Atlas to the Rabbit 600
热门求助领域 (近24小时)
化学 医学 生物 材料科学 工程类 有机化学 生物化学 物理 内科学 纳米技术 计算机科学 化学工程 复合材料 基因 遗传学 催化作用 物理化学 免疫学 量子力学 细胞生物学
热门帖子
关注 科研通微信公众号,转发送积分 3099914
求助须知:如何正确求助?哪些是违规求助? 2751373
关于积分的说明 7613446
捐赠科研通 2403368
什么是DOI,文献DOI怎么找? 1275253
科研通“疑难数据库(出版商)”最低求助积分说明 616318
版权声明 599053