Induction of cancer cell stemness by depletion of macrohistone H2A1 in hepatocellular carcinoma
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 spe...
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Veröffentlicht in: | Hepatology (Baltimore, Md.) Md.), 2018-02, Vol.67 (2), p.636-650 |
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creator | Lo Re, Oriana Fusilli, Caterina Rappa, Francesca Van Haele, Matthias Douet, Julien Pindjakova, Jana Rocha, Sura Wanessa Pata, Illar Valčíková, Barbora Uldrijan, Stjepan Yeung, Raymond S. Peixoto, Christina Alves Roskams, Tania Buschbeck, Marcus Mazza, Tommaso Vinciguerra, Manlio |
description | 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. (Hepatology 2018;67:636‐650). |
doi_str_mv | 10.1002/hep.29519 |
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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. (Hepatology 2018;67:636‐650).</description><identifier>ISSN: 0270-9139</identifier><identifier>EISSN: 1527-3350</identifier><identifier>DOI: 10.1002/hep.29519</identifier><identifier>PMID: 28913935</identifier><language>eng</language><publisher>United States: Wiley Subscription Services, Inc</publisher><subject>Cell proliferation ; Chemoresistance ; Chemotherapy ; Epigenetics ; Glycolysis ; Hepatocellular carcinoma ; Hepatology ; Histone H2A ; Hypoxia ; Liver cancer ; Metastases ; Phosphorylation ; Ribonucleic acid ; RNA ; Stem cell transplantation ; Stem cells ; Tumor cell lines ; Tumors</subject><ispartof>Hepatology (Baltimore, Md.), 2018-02, Vol.67 (2), p.636-650</ispartof><rights>2017 by the American Association for the Study of Liver Diseases.</rights><rights>2018 by the American Association for the Study of Liver Diseases.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4549-16a7e3833aa68d22f124ff4cd6cac6a8b3551a72752b431720b7b8f1942663403</citedby><cites>FETCH-LOGICAL-c4549-16a7e3833aa68d22f124ff4cd6cac6a8b3551a72752b431720b7b8f1942663403</cites><orcidid>0000-0002-1768-3894</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fhep.29519$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fhep.29519$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28913935$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lo Re, Oriana</creatorcontrib><creatorcontrib>Fusilli, Caterina</creatorcontrib><creatorcontrib>Rappa, Francesca</creatorcontrib><creatorcontrib>Van Haele, Matthias</creatorcontrib><creatorcontrib>Douet, Julien</creatorcontrib><creatorcontrib>Pindjakova, Jana</creatorcontrib><creatorcontrib>Rocha, Sura Wanessa</creatorcontrib><creatorcontrib>Pata, Illar</creatorcontrib><creatorcontrib>Valčíková, Barbora</creatorcontrib><creatorcontrib>Uldrijan, Stjepan</creatorcontrib><creatorcontrib>Yeung, Raymond S.</creatorcontrib><creatorcontrib>Peixoto, Christina Alves</creatorcontrib><creatorcontrib>Roskams, Tania</creatorcontrib><creatorcontrib>Buschbeck, Marcus</creatorcontrib><creatorcontrib>Mazza, Tommaso</creatorcontrib><creatorcontrib>Vinciguerra, Manlio</creatorcontrib><title>Induction of cancer cell stemness by depletion of macrohistone H2A1 in hepatocellular carcinoma</title><title>Hepatology (Baltimore, Md.)</title><addtitle>Hepatology</addtitle><description>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. (Hepatology 2018;67:636‐650).</description><subject>Cell proliferation</subject><subject>Chemoresistance</subject><subject>Chemotherapy</subject><subject>Epigenetics</subject><subject>Glycolysis</subject><subject>Hepatocellular carcinoma</subject><subject>Hepatology</subject><subject>Histone H2A</subject><subject>Hypoxia</subject><subject>Liver cancer</subject><subject>Metastases</subject><subject>Phosphorylation</subject><subject>Ribonucleic acid</subject><subject>RNA</subject><subject>Stem cell transplantation</subject><subject>Stem cells</subject><subject>Tumor cell lines</subject><subject>Tumors</subject><issn>0270-9139</issn><issn>1527-3350</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNp1kE9LwzAchoMobk4PfgEJeNFDt_xpmuQoY7rBQA96Dmmaso42mU2L7Nubus2D4CkQnt_D-74A3GI0xQiR2cbupkQyLM_AGDPCE0oZOgdjRDhKJKZyBK5C2CKEZErEJRgRMfxSNgZq5YredJV30JfQaGdsC42taxg62zgbAsz3sLC72p6gRpvWb6rQeWfhkjxhWDkYI-jOD4d9raNBt6ZyvtHX4KLUdbA3x3cCPp4X7_Nlsn59Wc2f1olJWSoTnGluqaBU60wUhJSYpGWZmiIz2mRa5JQxrDnhjOQpxZygnOeixLFPltEU0Ql4OHh3rf_sbehUU4UhjnbW90FFEiEmJCcRvf-Dbn3fupguUkJgKRnPIvV4oGLZEFpbql1bNbrdK4zUsLqKldXP6pG9Oxr7vLHFL3maOQKzA_BV1Xb_v0ktF28H5TcQ9IpR</recordid><startdate>201802</startdate><enddate>201802</enddate><creator>Lo Re, Oriana</creator><creator>Fusilli, Caterina</creator><creator>Rappa, Francesca</creator><creator>Van Haele, Matthias</creator><creator>Douet, Julien</creator><creator>Pindjakova, Jana</creator><creator>Rocha, Sura Wanessa</creator><creator>Pata, Illar</creator><creator>Valčíková, Barbora</creator><creator>Uldrijan, Stjepan</creator><creator>Yeung, Raymond S.</creator><creator>Peixoto, Christina Alves</creator><creator>Roskams, Tania</creator><creator>Buschbeck, Marcus</creator><creator>Mazza, Tommaso</creator><creator>Vinciguerra, Manlio</creator><general>Wiley Subscription Services, Inc</general><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7T5</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>H94</scope><scope>K9.</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-1768-3894</orcidid></search><sort><creationdate>201802</creationdate><title>Induction of cancer cell stemness by depletion of macrohistone H2A1 in hepatocellular carcinoma</title><author>Lo Re, Oriana ; 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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. (Hepatology 2018;67:636‐650).</abstract><cop>United States</cop><pub>Wiley Subscription Services, Inc</pub><pmid>28913935</pmid><doi>10.1002/hep.29519</doi><tpages>15</tpages><orcidid>https://orcid.org/0000-0002-1768-3894</orcidid><oa>free_for_read</oa></addata></record> |
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subjects | Cell proliferation Chemoresistance Chemotherapy Epigenetics Glycolysis Hepatocellular carcinoma Hepatology Histone H2A Hypoxia Liver cancer Metastases Phosphorylation Ribonucleic acid RNA Stem cell transplantation Stem cells Tumor cell lines Tumors |
title | Induction of cancer cell stemness by depletion of macrohistone H2A1 in hepatocellular carcinoma |
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