A novel KDM5A/MPC-1 signaling pathway promotes pancreatic cancer progression via redirecting mitochondrial pyruvate metabolism

生物 癌症研究 细胞生长 糖酵解 细胞培养 肿瘤进展 体内 癌变 细胞生物学 线粒体 新陈代谢 癌症 内分泌学 生物化学 遗传学
作者
Jiujie Cui,Ming Quan,Dacheng Xie,Yong Gao,Sushovan Guha,Michael B. Fallon,Jingde Chen,Keping Xie
出处
期刊:Oncogene [Springer Nature]
卷期号:39 (5): 1140-1151 被引量:49
标识
DOI:10.1038/s41388-019-1051-8
摘要

Mitochondrial pyruvate carrier 1 (MPC-1) appears to be a tumor suppressor. In this study, we determined the regulation of MPC-1 expression by Lysine demethylase 5A (KDM5A) and critical impact of this novel KDM5A/MPC-1 signaling on PDA progression. TCGA database, paired PDA and adjacent normal pancreatic tissues, PDA tissue array and cell lines were used to determine the levels of MPC-1 and KDM5A expression, and their relationship with the clinicopathologic characteristics and overall survival (OS) of PDA patients. Both in vitro and in vivo models were used to determine biologic impacts of MPC-1 and KDM5A on PDA and mitochondrial pyruvate metabolism, and the mechanism underling reduced MPC-1 expression in PDA. The expression of MPC-1 was decreased in PDA cell lines and tissues, and negatively associated with tumor poorer differentiation, lymph nodes metastasis, higher TNM stages, and patients' overall survival (OS). Functional analysis revealed that restored expression of MPC-1 suppressed the growth, invasion, migration, stemness and tumorigenicity. Re-expression of MPC-1 stimulated the mitochondrial pyruvate metabolism and inhibited glycolysis, while MPC-1-specific inhibitor UK5099 attenuated these effects. Furthermore, KDM5A bound directly to MPC-1 promoter region and transcriptionally suppressed the expression of MPC-1 via demethylation H3K4. Consistently, KDM5A expression was elevated in PDA and promoted PDA cell proliferation in vitro and tumor growth in vivo via suppressing the expression of MPC-1. The expression of KDM5A was inversely correlated with that of MPC-1 in PDA. KDM5A/MPC-1 signaling promoted PDA growth, invasion, migration, and stemness via inhibiting mitochondrial pyruvate metabolism. Targeting KDM5A/MPC-1 signaling may be an effective therapeutic strategy for PDA.
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
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
王勾勾完成签到,获得积分10
刚刚
韶华发布了新的文献求助10
1秒前
1秒前
2秒前
金箍棒完成签到,获得积分10
2秒前
自信的访云完成签到,获得积分10
2秒前
dropofwater完成签到,获得积分10
2秒前
嗯嗯完成签到 ,获得积分10
2秒前
雷雷完成签到,获得积分10
3秒前
果果完成签到 ,获得积分10
3秒前
杨天天完成签到,获得积分10
3秒前
3秒前
fei完成签到,获得积分10
3秒前
充电宝应助姿姿采纳,获得10
4秒前
沉吟碧云间丶完成签到,获得积分10
4秒前
wangc发布了新的文献求助30
4秒前
科研通AI5应助仪锦文采纳,获得10
4秒前
5秒前
zhi完成签到,获得积分10
5秒前
6秒前
6秒前
柠檬杨完成签到,获得积分10
7秒前
7秒前
彭于晏应助姜梦采纳,获得10
7秒前
高会和发布了新的文献求助10
7秒前
8秒前
8秒前
tjl完成签到,获得积分10
8秒前
小二郎应助tanwenbin采纳,获得10
8秒前
小二郎应助tanwenbin采纳,获得10
8秒前
隐形曼青应助tanwenbin采纳,获得10
9秒前
9秒前
9秒前
是韩东发布了新的文献求助20
10秒前
Akim应助西瓜籽采纳,获得10
10秒前
含蓄的大白完成签到,获得积分20
10秒前
zzz发布了新的文献求助10
10秒前
1461644768发布了新的文献求助30
10秒前
YUYUFENG发布了新的文献求助10
10秒前
劲爆巧克力完成签到,获得积分10
10秒前
高分求助中
Technologies supporting mass customization of apparel: A pilot project 600
Chinesen in Europa – Europäer in China: Journalisten, Spione, Studenten 500
Arthur Ewert: A Life for the Comintern 500
China's Relations With Japan 1945-83: The Role of Liao Chengzhi // Kurt Werner Radtke 500
Two Years in Peking 1965-1966: Book 1: Living and Teaching in Mao's China // Reginald Hunt 500
材料概论 周达飞 ppt 500
Introduction to Strong Mixing Conditions Volumes 1-3 500
热门求助领域 (近24小时)
化学 材料科学 医学 生物 工程类 有机化学 物理 生物化学 纳米技术 计算机科学 化学工程 内科学 复合材料 物理化学 电极 遗传学 量子力学 基因 冶金 催化作用
热门帖子
关注 科研通微信公众号,转发送积分 3808401
求助须知:如何正确求助?哪些是违规求助? 3353139
关于积分的说明 10363475
捐赠科研通 3069342
什么是DOI,文献DOI怎么找? 1685478
邀请新用户注册赠送积分活动 810551
科研通“疑难数据库(出版商)”最低求助积分说明 766193