Induction of cancer cell stemness by depletion of macrohistone H2A1 in hepatocellular carcinoma

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00159816%3A_____%2F18%3A00067249" target="_blank" >RIV/00159816:_____/18:00067249 - isvavai.cz</a>

Alternative codes found

RIV/00216224:14110/18:00102119

Result on the web

<a href="https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep.29519" target="_blank" >https://aasldpubs.onlinelibrary.wiley.com/doi/full/10.1002/hep.29519</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1002/hep.29519" target="_blank" >10.1002/hep.29519</a>

Result language

angličtina

Original language name

Induction of cancer cell stemness by depletion of macrohistone H2A1 in hepatocellular carcinoma

Original language description

Hepatocellular carcinomas (HCC) contain a sub-population of cancer stem cells (CSCs), which exhibit stem-cell like features and are responsible for tumor relapse, metastasis, and chemoresistance. The development of effective treatments for HCC will depend on a molecular-level understanding of the specific pathways driving CSC emergence and stemness. MacroH2A1 is a variant of the histone H2A and an epigenetic regulator of stem cell function, where it promotes differentiation and, conversely, acts as a barrier to somatic cell reprogramming. Here we focused on the role played by the histone variant macroH2A1 as a potential epigenetic factor promoting CSC differentiation. In human HCC sections we uncovered a significant correlation between low frequencies of macroH2A1 staining and advanced, aggressive HCC subtypes with poorly-differentiated tumor phenotypes. Using HCC cell lines we found that shRNA-mediated macroH2A1 knock-down induces acquisition of CSC-like features, including the growth of significantly larger and less-differentiated tumors when injected into nude mice. MacroH2A1-depleted HCC cells also exhibited reduced proliferation, resistance to chemotherapeutic agents, and stem-like metabolic changes consistent with enhanced hypoxia responses and increased glycolysis. The loss of macroH2A1 increased expression of a panel of stemness-associated genes, and drove hyper-activation of the NF-κBp65 pathway. Blocking phosphorylation of NF-κBp65 on Ser536 inhibited the emergence of CSC-like features in HCC cells knocked-down for macroH2A1. CONCLUSION: the absence of histone variant macroH2A1 confers a CSC-like phenotype to HCC cells in vitro and in vivo that depends on Ser536 phosphorylation of NF-κBp65. This pathway may hold valuable targets for the development of CSC-focused treatments for HCC. This article is protected by copyright. All rights reserved.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

30219 - Gastroenterology and hepatology

Project

<a href="/en/project/EF15_003%2F0000492" target="_blank" >EF15_003/0000492: Unveiling the molecular determinants of agingto design new therapeutics</a><br>

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2018

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Hepatology

ISSN

0270-9139

e-ISSN

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Volume of the periodical

67

Issue of the periodical within the volume

2

Country of publishing house

US - UNITED STATES

Number of pages

15

Pages from-to

636-650

UT code for WoS article

000422694900020

EID of the result in the Scopus database

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