EZH2 is a key component of hepatoblastoma tumor cell growth

Abstract

BackgroundEnhancer of zeste homolog 2 (EZH2) catalyzes the trimethylation of histone H3 at lysine 27 via the polycomb recessive complex 2 (PRC2) and plays a time‐specific role in normal fetal liver development. EZH2 is overexpressed in hepatoblastoma (HB), an embryonal tumor. EZH2 can also promote tumorigenesis via a noncanonical, PRC2‐independent mechanism via proto‐oncogenic, direct protein interaction, including β‐catenin. We hypothesize that the pathological activation of EZH2 contributes to HB propagation in a PRC2‐independent manner.Methods and resultsWe demonstrate that EZH2 promotes proliferation in HB tumor‐derived cell lines through interaction with β‐catenin. Although aberrant EZH2 expression occurs, we determine that both canonical and noncanonical EZH2 signaling occurs based on specific gene‐expression patterns and interaction with SUZ12, a PRC2 component, and β‐catenin. Silencing and inhibition of EZH2 reduce primary HB cell proliferation.ConclusionsEZH2 overexpression promotes HB cell proliferation, with both canonical and noncanonical function detected. However, because EZH2 directly interacts with β‐catenin in human tumors and EZH2 overexpression is not equal to SUZ12, it seems that a noncanonical mechanism is contributing to HB pathogenesis. Further mechanistic studies are necessary to elucidate potential pathogenic downstream mechanisms and translational potential of EZH2 inhibitors for the treatment of HB.

Chromatin modifiers in human disease: from functional roles to regulatory mechanisms

“…Proto-oncogenes transform normal cells into functional oncogenes in four ways: acquisition of strong promoters and enhancers, chromosomal translocations, gene amplification, and point mutations, all of which are inseparable from the regulation of chromatin modifiers. For example, crosstalk between histone-modifying enzymes and enhancers promotes the activation of proto-oncogenes, causing tumors such as liver, breast, and colorectal cancers [89][90][91][92]. The G protein-coupled receptor A2A activates the proto-oncogene MYC to promote proline synthesis, and the increased level of proline metabolism recruits histone acetylases SIRT6 and SIRT7 to mediate the level of H3 deacetylation in prostate cancer cells, triggering the transformation of prostate adenocarcinoma into a neuroendocrine tumor [93].…”

Organoids as a new approach for improving pediatric cancer research

“…Another model of HB PDOs was established by Glaser and colleagues, who used cells isolated from PDXs, to study the relationship between EXH2 and canonical Wnt signaling. In particular they silenced EZH2 genes by siRNA and reported that HB control cells form organoid while treated cells showed reduced cell aggregation into organoids, indicating as EZH2 inhibition have a potential role in HB pathogenesis ( 88 ). There is also another study that similar to the previously used HB organoids to test antitumoral efficacy in HB.…”