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:103
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.
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