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

Kód výsledku v 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>

Nalezeny alternativní kódy

RIV/00216224:14110/18:00102119

Výsledek na webu

<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>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30219 - Gastroenterology and hepatology

Projekt

<a href="/cs/project/EF15_003%2F0000492" target="_blank" >EF15_003/0000492: Mapování molekulární podstaty procesů stárnutí pro vývoj nových léčebných metod</a><br>

Návaznosti

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

Rok uplatnění

2018

Kód důvěrnosti údajů

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

Název periodika

Hepatology

ISSN

0270-9139

e-ISSN

—

Svazek periodika

67

Číslo periodika v rámci svazku

2

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

15

Strana od-do

636-650

Kód UT WoS článku

000422694900020

EID výsledku v databázi Scopus

—