Abstract
H2A.Z is a highly conserved H2A variant, and two distinct H2A.Z isoforms, H2A.Z.1 and H2A.Z.2, have been identified as products of two non-allelic genes, H2AFZ and H2AFV. H2A.Z has been reported to be overexpressed in breast, prostate and bladder cancers, but most studies did not clearly distinguish between isoforms. One recent study reported a unique role for the H2A.Z isoform H2A.Z.2 as a driver of malignant melanoma. Here we first report that H2A.Z.1 plays a pivotal role in the liver tumorigenesis by selectively regulating key molecules in cell cycle and epithelial-mesenchymal transition (EMT). H2AFZ expression was significantly overexpressed in a large cohort of hepatocellular carcinoma (HCC) patients, and high expression of H2AFZ was significantly associated with their poor prognosis. H2A.Z.1 overexpression was demonstrated in a subset of human HCC and cell lines. H2A.Z.1 knockdown suppressed HCC cell growth by transcriptional deregulation of cell cycle proteins and caused apoptotic cell death of HCC cells. We also observed that H2A.Z.1 knockdown reduced the metastatic potential of HCC cells by selectively modulating epithelial-mesenchymal transition regulatory proteins such as E-cadherin and fibronectin. In addition, H2A.Z.1 knockdown reduced the in vivo tumor growth rate in a mouse xenograft model. In conclusion, our findings suggest the oncogenic potential of H2A.Z.1 in liver tumorigenesis and that it plays established role in accelerating cell cycle transition and EMT during hepatocarcinogenesis. This makes H2A.Z.1 a promising target in liver cancer therapy.
Highlights
Genomic DNA in eukaryotic cells is packaged into chromatin, with the nucleosome being the smallest subunit that contains canonical histones: H2A, H2B, H3, H4, and H1
A recent study reported a unique role for the H2A.Z isoform H2A.Z.2 as a driver of malignant melanoma [15]
We aimed to characterize the role of H2A.Z deregulation in liver tumorigenesis and determine which H2A.Z isoform might be involved in this process
Summary
Genomic DNA in eukaryotic cells is packaged into chromatin, with the nucleosome being the smallest subunit that contains canonical histones: H2A, H2B, H3, H4, and H1. H2A.Z exchange is promoted by ATPdependent exchange complexes, including Snf2-Related CREBBP activator (SRCAP) [6] and p400/Tip complex [7], and it plays a major role in critical biological processes, such as chromosome segregation [8], cell cycle progression [9] and maintaining heterochromatin/euchromatin status [10] It is so far the only histone that has been shown to be indispensable for survival in many organisms, and only a single gene copy is present in invertebrates, two distinct gene copies exist in vertebrates [11]. In the context of tumorigenesis, H2A.Z is overexpressed in breast, prostate, and bladder cancers, where in some cases, it increases proliferation [13] These studies either focused solely on H2A.Z.1, or did not clearly distinguish between isoforms
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