Defeating EpCAM+ liver cancer stem cells by targeting chromatin remodeling enzyme CHD4 in human hepatocellular carcinoma

Nio, Kouki; Yamashita, Taro; Okada, Hikari; Kondo, Masanari; Hayashi, Takuo; Hara, Yukio; Nomura, Yoshimoto; Zeng, Shengkui; Yoshida, Minoru; Hayashi, Tomoyuki; Sunagozaka, Hajime; Oishi, Naoki; Honda, Masao

doi:10.1016/j.jhep.2015.06.009

Cited by 76 publications

(50 citation statements)

References 39 publications

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“…This role may be integral to some oncogenic properties of CHD4 shown by others (Fu et al, 2011; Nio et al, 2015; Sperlazza et al, 2015). We link CHD4 recruitment to DDR processes induced by laser micro-irradiation to trigger SSBs and DSBs, pure DSBs produced by either site-specific restriction endonuclease cutting or CRISPR-CAS technology, and SSBs in the context of BER repair during oxidative damage.…”

Section: Discussionmentioning

confidence: 93%

CHD4 Has Oncogenic Functions in Initiating and Maintaining Epigenetic Suppression of Multiple Tumor Suppressor Genes

et al. 2017

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SUMMARY An oncogenic role for CHD4, a NuRD component, is defined for initiating and supporting tumor suppressor gene (TSG) silencing in human colorectal cancer. CHD4 recruits repressive chromatin proteins to sites of DNA damage repair, including DNA methyltransferases where it imposes de novo DNA methylation. At TSGs, CHD4 retention helps maintain DNA hypermethylation-associated transcriptional silencing. CHD4 is recruited by the excision repair protein OGG1 for oxidative damage to interact with the damage-induced base 8-hydroxydeoxyguanosine (8-OHdG), while ZMYND8 recruits it to double-strand breaks. CHD4 knockdown activates silenced TSGs, revealing their role for blunting colorectal cancer cell proliferation, invasion, and metastases. High CHD4 and 8-OHdG levels plus low expression of TSGs strongly correlates with early disease recurrence and decreased overall survival.

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Section: Discussionmentioning

confidence: 93%

CHD4 Has Oncogenic Functions in Initiating and Maintaining Epigenetic Suppression of Multiple Tumor Suppressor Genes

et al. 2017

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“…Recently, the identification of CSCs in many malignancies, including HCC, has renovated our view of malignant tumors [10]. CSCs, also known as tumor initiating cells, have stemness characteristics such as self-renewal and differentiation [39]. They have the capacity to form neoplastic and metastatic tumors, and may account for the high postsurgical recurrence rates [40].…”

Section: Discussionmentioning

confidence: 99%

Long Noncoding RNA lncCAMTA1 Promotes Proliferation and Cancer Stem Cell-Like Properties of Liver Cancer by Inhibiting CAMTA1

Ding

Wang

et al. 2016

IJMS

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Hepatocellular carcinoma (HCC) is the most common subtype of liver malignancy, and it is characterized by poor prognosis because of cancer stem cell (CSC)-mediated high postsurgical recurrence rates. Thus, targeting CSCs, or HCC cells with CSC-like properties, is an effective strategy for HCC therapy. Here, using long noncoding RNA (lncRNA) microarray analysis, we identified a novel lncRNA termed lncCAMTA1 that is increased in both liver CSCs and HCC. High lncCAMTA1 expression in HCC indicates poor clinical outcome. In vitro and in vivo functional experiments showed that overexpression of lncCAMTA1 promotes HCC cell proliferation, CSC-like properties, and tumorigenesis. Conversely, depletion of lncCAMTA1 inhibits HCC cell proliferation, CSC-like properties, and tumorigenesis. Mechanistically, we demonstrated that lncCAMTA1 physically associates with the calmodulin binding transcription activator 1 (CAMTA1) promoter, induces a repressive chromatin structure, and inhibits CAMTA1 transcription. Furthermore, CAMTA1 is required for the effects of lncCAMTA1 on HCC cell proliferation and CSC-like properties, and the expression of lncCAMTA1 and CAMTA1 is significantly negatively correlated in HCC tissues. Collectively, our study revealed the important roles and underlying molecular mechanisms of lncCAMTA1 on HCC, and suggested that lncCAMTA1 could be an effective prognostic factor and a potential therapeutic target for HCC.

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“…Wnt-β-catenin [5,104] , CHD4 [105] , OSM [106] , ATRA [107] , EZH2 [108] , miR-155 [109] , miR-181 [111] , miR-216a/217/ PTEN /SMAD7 [110] CD47 CTSS/PAR2 [6,120] , NF-κB [122] , SIRPα [119]…”

Section: Epcammentioning

confidence: 99%

“…EpCAM is a target gene in Wnt-β-catenin signaling pathway [5,104] . Chemoresistance as well as stemness of EpCAM+ LCSCs are modulated by abnormal expression of CHD4 [105] , OSM [106] , ATRA [107] , EZH2 [108] . A group of microRNAs including miR-181, miR-155, miR-181, miR-216a/217 have been found involved in regulating stemness of EpCAM+ HCC cells [109][110][111] .…”

Section: Epcammentioning

confidence: 99%

Advances in surface markers of liver cancer stem cell

Zhang¹,

Gong²,

Yan³

et al. 2019

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Liver cancer stem cells (LCSCs), a small subpopulation that constitutes liver cancer heterogeneity, play a vital role in cancer initiation, invasion, recurrence, metastasis, and resistance to chemo-radiotherapy. It is believed that therapies targeting LCSCs can improve the efficacy of conventional chemotherapy and radiotherapy by completely eliminating tumors while preventing recurrence. Therefore, during last decades, numerous surface markers for LCSCs have been identified and characterized in many subtypes of liver cancer, especially in hepatocellular carcinoma (HCC). These well-recognized surface markers significantly promote the therapeutic efficacy that identifies, targets and destroys LCSCs. Meanwhile, there have been intensive studies that aim to investigate the molecular mechanism of how stemness contributes to liver cancer relapse, recurrence and resistance. However, liver cancer stemness seems to be regulated by a hierarchical organization and crosstalk of a wide variety of signaling pathways. Using individual or few LCSC surface markers may not be able to completely reveal the intrinsic stemness hierarchy. From an integrated perspective, understanding of recent advances in LCSC surface markers remains important and urgent. In this review, we concentrate on demonstrating the indispensable roles of LCSC surface markers in identification and characterization of multiple cancer stages including initiation, invasion, metastasis, resistance and highlighting the cutting-edge therapeutic strategies against cancer stem cells in HCC.

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Defeating EpCAM+ liver cancer stem cells by targeting chromatin remodeling enzyme CHD4 in human hepatocellular carcinoma

Cited by 76 publications

References 39 publications

CHD4 Has Oncogenic Functions in Initiating and Maintaining Epigenetic Suppression of Multiple Tumor Suppressor Genes

CHD4 Has Oncogenic Functions in Initiating and Maintaining Epigenetic Suppression of Multiple Tumor Suppressor Genes

Long Noncoding RNA lncCAMTA1 Promotes Proliferation and Cancer Stem Cell-Like Properties of Liver Cancer by Inhibiting CAMTA1

Advances in surface markers of liver cancer stem cell

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