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EBioMedicine. 2017 Jul;21:104-116. doi: 10.1016/j.ebiom.2017.06.007. Epub 2017 Jun 8.

Histone Chaperone ASF1A Predicts Poor Outcomes for Patients With Gastrointestinal Cancer and Drives Cancer Progression by Stimulating Transcription of β-Catenin Target Genes.

Author information

1
Central Research Laboratory, Shandong University, Second Hospital, Jinan, PR China; Department of Medicine, Division of Hematology, and Center for Molecular Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden. Electronic address: liangxm@sdu.edu.cn.
2
Department of Medicine, Division of Hematology, and Center for Molecular Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.
3
Central Research Laboratory, Shandong University, Second Hospital, Jinan, PR China.
4
Department of Microbiology, School of Medicine, Shandong University, Jinan, PR China.
5
Central Research Laboratory, Shandong University, Second Hospital, Jinan, PR China; Department of Medicine, Division of Hematology, and Center for Molecular Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden. Electronic address: Dawei.Xu@ki.se.

Abstract

Epigenetic mechanisms play a key role in gastrointestinal cancer (GIC) development and progression, and most studies have been focused on aberrant DNA methylation and histone modifying enzymes. However, the histone H3-H4 chaperone ASF1A is an important factor regulating chromatin assembling and gene transcription, while it is currently unclear whether ASF1A is involved in cancer pathogenesis. The present study is thus designed to address this issue. Here we showed that ASF1A expression was widespread in GIC-derived cell lines and up-regulated in primary GIC. Higher levels of ASF1A expression predicted significantly shorter patient overall survival in colorectal cancer (P=0.0012). The further analyses of the GEO dataset validate higher ASF1A expression as a prognostic factor for CRC patients. Mechanistically, ASF1A interacted with β-catenin and promoted the transcription of β-catenin target genes including c-MYC, cyclin D1, ZEB1 and LGR5, thereby stimulating proliferation, stemness and migration/invasion of GIC cells. β-Catenin inhibition abolished these effects of ASF1A. Moreover, the ASF1A-β-catenin-ZEB1 axis down-regulated E-Cadherin expression, thereby contributing to enhanced migration/invasion of GIC cells. ASF1A over-expression and depletion facilitated and inhibited in vivo tumor growth and/or metastasis in mouse xenograft models, respectively. Taken together, ASF1A is aberrantly over-expressed in GIC tumors and plays key roles in GIC development and progression by stimulating the transcription of β-catenin target genes. ASF1A may thus be a novel target for GIC therapy and a potential prognostic marker.

KEYWORDS:

ASF1A; Gastrointestinal cancer; Histone modification; ZEB1; β-Catenin

PMID:
28625518
PMCID:
PMC5514402
DOI:
10.1016/j.ebiom.2017.06.007
[Indexed for MEDLINE]
Free PMC Article

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