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

J 2018

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

LO RE, Oriana, C. FUSILLI, F. RAPPA, M. VAN HAELE, J. DOUET et. al.

Basic information

Original name

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

Authors

LO RE, Oriana (380 Italy, belonging to the institution), C. FUSILLI (380 Italy), F. RAPPA (380 Italy), M. VAN HAELE (56 Belgium), J. DOUET (724 Spain), J. PINDJAKOVA (203 Czech Republic), S.W. ROCHA (76 Brazil), I. PATA (233 Estonia), Barbora VALČÍKOVÁ (203 Czech Republic, belonging to the institution), Stjepan ULDRIJAN (203 Czech Republic, belonging to the institution), R.S. YEUNG (840 United States of America), C.A. PEIXOTO (76 Brazil), T. ROSKAMS (56 Belgium), M. BUSCHBECK (724 Spain), T. MAZZA (380 Italy) and M. VINCIGUERRA (826 United Kingdom of Great Britain and Northern Ireland, guarantor)

Edition

Hepatology, Philadelphia, Saunders, 2018, 0270-9139

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

30219 Gastroenterology and hepatology

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

Impact factor

Impact factor: 14.971

RIV identification code

RIV/00216224:14110/18:00102119

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1002/hep.29519

UT WoS

000422694900020

Keywords in English

histone variants; epigenetics; hepatocellular carcinoma; cancer stem cells

Abstract

V originále

Hepatocellular carcinomas (HCC) contain a subpopulation 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 short hairpin RNA-mediated macroH2A1 knockdown 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 hypoxic responses and increased glycolysis. The loss of macroH2A1 increased expression of a panel of stemness-associated genes and drove hyperactivation of the nuclear factor kappa B p65 pathway. Blocking phosphorylation of nuclear factor kappa B p65 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 nuclear factor kappa B p65; this pathway may hold valuable targets for the development of CSC-focused treatments for HCC.

Citovat

LO RE, Oriana, C. FUSILLI, F. RAPPA, M. VAN HAELE, J. DOUET, J. PINDJAKOVA, S.W. ROCHA, I. PATA, Barbora VALČÍKOVÁ, Stjepan ULDRIJAN, R.S. YEUNG, C.A. PEIXOTO, T. ROSKAMS, M. BUSCHBECK, T. MAZZA and M. VINCIGUERRA. Induction of cancer cell stemness by depletion of macrohistone H2A1 in hepatocellular carcinoma. Hepatology. Philadelphia: Saunders, 2018, vol. 67, No 2, p. 636-650. ISSN 0270-9139. Available from: https://dx.doi.org/10.1002/hep.29519.

@article{1397146,
   author = {Lo Re, Oriana and Fusilli, C. and Rappa, F. and Van Haele, M. and Douet, J. and Pindjakova, J. and Rocha, S.W. and Pata, I. and Valčíková, Barbora and Uldrijan, Stjepan and Yeung, R.S. and Peixoto, C.A. and Roskams, T. and Buschbeck, M. and Mazza, T. and Vinciguerra, M.},
   article_location = {Philadelphia},
   article_number = {2},
   doi = {http://dx.doi.org/10.1002/hep.29519},
   keywords = {histone variants; epigenetics; hepatocellular carcinoma; cancer stem cells},
   language = {eng},
   issn = {0270-9139},
   journal = {Hepatology},
   title = {Induction of cancer cell stemness by depletion of macrohistone H2A1 in hepatocellular carcinoma},
   volume = {67},
   year = {2018}
}

TY  - JOUR
ID  - 1397146
AU  - Lo Re, Oriana - Fusilli, C. - Rappa, F. - Van Haele, M. - Douet, J. - Pindjakova, J. - Rocha, S.W. - Pata, I. - Valčíková, Barbora - Uldrijan, Stjepan - Yeung, R.S. - Peixoto, C.A. - Roskams, T. - Buschbeck, M. - Mazza, T. - Vinciguerra, M.
PY  - 2018
TI  - Induction of cancer cell stemness by depletion of macrohistone H2A1 in hepatocellular carcinoma
JF  - Hepatology
VL  - 67
IS  - 2
SP  - 636-650
EP  - 636-650
PB  - Saunders
SN  - 02709139
KW  - histone variants
KW  - epigenetics
KW  - hepatocellular carcinoma
KW  - cancer stem cells
N2  - Hepatocellular carcinomas (HCC) contain a subpopulation 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 short hairpin RNA-mediated macroH2A1 knockdown 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 hypoxic responses and increased glycolysis. The loss of macroH2A1 increased expression of a panel of stemness-associated genes and drove hyperactivation of the nuclear factor kappa B p65 pathway. Blocking phosphorylation of nuclear factor kappa B p65 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 nuclear factor kappa B p65; this pathway may hold valuable targets for the development of CSC-focused treatments for HCC.
ER  -

LO RE, Oriana, C. FUSILLI, F. RAPPA, M. VAN HAELE, J. DOUET, J. PINDJAKOVA, S.W. ROCHA, I. PATA, Barbora VALČÍKOVÁ, Stjepan ULDRIJAN, R.S. YEUNG, C.A. PEIXOTO, T. ROSKAMS, M. BUSCHBECK, T. MAZZA and M. VINCIGUERRA. Induction of cancer cell stemness by depletion of macrohistone H2A1 in hepatocellular carcinoma. \textit{Hepatology}. Philadelphia: Saunders, 2018, vol.~67, No~2, p.~636-650. ISSN~0270-9139. Available from: https://dx.doi.org/10.1002/hep.29519.

Detailed Information on Publication Record