DNMT1-mediated methylation of BEX1 regulates stemness and tumorigenicity in liver cancer

Wnt信号通路 癌症干细胞 癌症研究 DNA甲基化 DNMT1型 甲基化 生物 肝癌 干细胞 甲基转移酶 肝细胞癌 信号转导 细胞生物学 基因表达 遗传学 基因
作者
Qian Wang,Ning Liang,Tao Yang,Jing Li,Jing Li,Qian Huang,Chen Wu,Ligang Sun,Xile Zhou,Xiao-bin Cheng,Long Zhao,Gang Wang,Zhangqian Chen,Xianli He,Chaoxu Liu
出处
期刊:Journal of Hepatology [Elsevier BV]
卷期号:75 (5): 1142-1153 被引量:108
标识
DOI:10.1016/j.jhep.2021.06.025
摘要

Background & Aims

Hepatoblastoma (HB) and hepatocellular carcinoma (HCC) both exhibit notable cancer stem cell (CSC) features. Moreover, the development of both diseases is closely associated with the presence of CSCs. We investigated the role of brain-expressed X-linked protein 1 (BEX1) in regulating the CSC properties of HB and a subtype of HCC with high CSC features (CSC-HCC).

Methods

Stemness scores were analyzed in 5 murine HCC models. A subpopulation of BEX1-positive cells and BEX1-negative cells were sorted from HCC cell lines, and subjected to transcriptome analysis. The expression and function of BEX1 was examined via western blotting, sphere formation assays, and xenograft tumor models.

Results

We identified BEX1 as a novel CSC marker that was required for the self-renewal of liver CSCs. Furthermore, zebularine, a potent DNMT1 inhibitor, can induce the reactivation of BEX1 by removing epigenetic inhibition. Notably, BEX1 was highly expressed in patients with HB and CSC-HCC, but not in patients with non-CSC HCC. Moreover, DNMT1-mediated methylation of the BEX1 promoter resulted in differential BEX1 expression patterns in patients with HB, CSC-HCC, and non-CSC-HCC. Mechanistically, BEX1 interacted with RUNX3 to block its inhibition of β-catenin transcription, which led to the activation of Wnt/β-catenin signaling, and stemness maintenance in both HB and CSC-HCC. In contrast, downregulated BEX1 expression released RUNX3 and inhibited the activation of Wnt/β-catenin signaling in non-CSC-HCC.

Conclusion

BEX1, under the regulation of DNMT1, is necessary for the self-renewal and maintenance of liver CSCs through activation of Wnt/β-catenin signaling, rendering BEX1 a potentially valuable therapeutic target in both HB and CSC-HCC.

Lay summary

Cancer stem cells (CSCs) contribute to a high rate of cancer recurrence, as well as resistance to conventional therapies. However, the regulatory mechanisms underlying their self-renewal remains elusive. Herein, we have reported that BEX1 plays a key role in regulating CSC properties in different types of liver cancer. Targeting BEX1-mediated Wnt/β-catenin signaling may help to address the high rate of recurrence, and heterogeneity of liver cancer.
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
PDF的下载单位、IP信息已删除 (2025-6-4)

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
2秒前
My完成签到,获得积分10
2秒前
孙颖莎粉丝完成签到,获得积分10
2秒前
尼古拉耶维奇完成签到,获得积分10
2秒前
阿卡宁发布了新的文献求助10
3秒前
4秒前
温柔翰完成签到,获得积分10
5秒前
文龙完成签到 ,获得积分10
5秒前
6秒前
Xiaopan完成签到,获得积分10
6秒前
xiaoming发布了新的文献求助200
7秒前
7秒前
QT完成签到,获得积分20
8秒前
朱华彪完成签到,获得积分10
8秒前
活在当下发布了新的文献求助10
8秒前
8秒前
haha发布了新的文献求助10
9秒前
aurora完成签到 ,获得积分10
10秒前
茉莉完成签到,获得积分10
10秒前
123完成签到,获得积分10
12秒前
12秒前
wwewew完成签到,获得积分10
13秒前
saying发布了新的文献求助10
13秒前
123123完成签到,获得积分10
13秒前
隐形曼青应助阿卡宁采纳,获得10
14秒前
负责紊完成签到,获得积分10
14秒前
善良的火发布了新的文献求助10
16秒前
haha完成签到,获得积分10
16秒前
18秒前
sugar完成签到,获得积分10
19秒前
活在当下完成签到,获得积分10
19秒前
21秒前
ssy发布了新的文献求助10
21秒前
小嘉贞完成签到,获得积分10
23秒前
鸡蛋黄完成签到,获得积分10
24秒前
温纲完成签到,获得积分10
25秒前
lalafish完成签到,获得积分10
25秒前
研友_nV2Kyn完成签到,获得积分10
26秒前
王冉冉发布了新的文献求助10
26秒前
铁甲小宝完成签到,获得积分10
27秒前
高分求助中
【提示信息,请勿应助】关于scihub 10000
Les Mantodea de Guyane: Insecta, Polyneoptera [The Mantids of French Guiana] 3000
徐淮辽南地区新元古代叠层石及生物地层 3000
The Mother of All Tableaux: Order, Equivalence, and Geometry in the Large-scale Structure of Optimality Theory 3000
Global Eyelash Assessment scale (GEA) 1000
Picture Books with Same-sex Parented Families: Unintentional Censorship 550
Research on Disturbance Rejection Control Algorithm for Aerial Operation Robots 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 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 遗传学 基因 物理化学 催化作用 冶金 细胞生物学 免疫学
热门帖子
关注 科研通微信公众号,转发送积分 4038524
求助须知:如何正确求助?哪些是违规求助? 3576221
关于积分的说明 11374737
捐赠科研通 3305912
什么是DOI,文献DOI怎么找? 1819354
邀请新用户注册赠送积分活动 892688
科研通“疑难数据库(出版商)”最低求助积分说明 815048