Oncogenic potential of histone-variant H2A.Z.1 and its regulatory role in cell cycle and epithelial-mesenchymal transition in liver cancer

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.

The Histone Variant H2A.Z Is a Master Regulator of the Epithelial-Mesenchymal Transition

“…The findings of this study will have important implications in understanding cancer progression, given that the conversion of epithelial cells to mesenchymal cells is required for tumor metastasis. However, the role of H2A.Z in cancer (Svotelis et al, 2010) may be even more complex than first envisaged; it was recently shown that the knockdown of H2A.Z expression in human liver cancer cell lines inhibits the expression of fibronectin (a mesenchymal marker gene) and activates E-cadherin expression (an epithelial marker gene) (Yang et al, 2016), which contrasts with our observations. Taken together, these findings suggest that the function of H2A.Z may change during cancer progression, according to cancer type.…”

Recognition of histone acetylation by the GAS41 YEATS domain promotes H2A.Z deposition in non-small cell lung cancer

“…occupancy, which is important because H2A.Z has been shown to possess an oncogenic role regulating similar sets of genes in different types of tumors. For example, H2A.Z is both overexpressed in and enriched at promoters of cell cycle regulatory genes in bladder cancer (Kim et al 2013), liver cancer (Yang et al 2016), and melanoma (Vardabasso et al 2015). Importantly, although H2A.Z is enriched at both active and poised gene promoters, acetylated H2A.Z is associated exclusively with gene activation (Ku et al 2012;Valdes-Mora et al 2012).…”

SMYD3-Mediated H2A.Z.1 Methylation Promotes Cell Cycle and Cancer Proliferation

“…H2A.Z is an oncogenic histone variant that is overexpressed in breast, colorectal, liver, and bladder cancers (20)(21)(22)(23). Two isoforms of H2A.Z, H2A.Z.1 and H2A.Z.2, have been identified as products of two nonallelic genes (24,25), and each can execute isoform-specific function.…”