Collagen Prolyl Hydroxylation-Dependent Metabolic Perturbation Governs Epigenetic Remodeling and Mesenchymal Transition in Pluripotent and Cancer Cells
Collagen prolyl hydroxylation (CPH), which is catalyzed by prolyl 4-hydroxylase (P4H), is the most prevalent posttranslational modification in humans and requires vitamin C (VitC). Here, we demonstrate that CPH acts as an epigenetic modulator of cell plasticity. Increased CPH induced global DNA/hist...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2019-07, Vol.79 (13), p.3235-3250 |
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| creator | D'Aniello, Cristina Cermola, Federica Palamidessi, Andrea Wanderlingh, Luca G Gagliardi, Miriam Migliaccio, Agnese Varrone, Francesca Casalino, Laura Matarazzo, Maria R De Cesare, Dario Scita, Giorgio Patriarca, Eduardo J Minchiotti, Gabriella |
| description | Collagen prolyl hydroxylation (CPH), which is catalyzed by prolyl 4-hydroxylase (P4H), is the most prevalent posttranslational modification in humans and requires vitamin C (VitC). Here, we demonstrate that CPH acts as an epigenetic modulator of cell plasticity. Increased CPH induced global DNA/histone methylation in pluripotent stem and tumor cells and promoted cell state transition (CST). Interfering with CPH by either genetic ablation of P4H subunit alpha-2 (P4HA2) or pharmacologic treatment reverted epigenetic changes and antagonized CST. Mechanistically, we suggest that CPH modifies the epigenetic landscape by reducing VitC for DNA and histone demethylases. Repurposed drugs targeting CPH-mediated metabolic perturbation, such as the antiasthmatic budesonide, blocked metastatic dissemination of breast cancer cells
by preventing mesenchymal transition. Our study provides mechanistic insights into how metabolic cues and epigenetic factors integrate to control CST and paves the way for the development of novel antimetastatic strategies. SIGNIFICANCE: A phenotype-based high-throughput screening reveals unforeseen metabolic control of cell plasticity and identifies budesonide as a drug candidate for metastatic cancer.
http://cancerres.aacrjournals.org/content/canres/79/13/3235/F1.large.jpg. |
| doi_str_mv | 10.1158/0008-5472.CAN-18-2070 |
| format | Article |
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by preventing mesenchymal transition. Our study provides mechanistic insights into how metabolic cues and epigenetic factors integrate to control CST and paves the way for the development of novel antimetastatic strategies. SIGNIFICANCE: A phenotype-based high-throughput screening reveals unforeseen metabolic control of cell plasticity and identifies budesonide as a drug candidate for metastatic cancer.
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by preventing mesenchymal transition. Our study provides mechanistic insights into how metabolic cues and epigenetic factors integrate to control CST and paves the way for the development of novel antimetastatic strategies. SIGNIFICANCE: A phenotype-based high-throughput screening reveals unforeseen metabolic control of cell plasticity and identifies budesonide as a drug candidate for metastatic cancer.
http://cancerres.aacrjournals.org/content/canres/79/13/3235/F1.large.jpg.</description><subject>Breast Neoplasms - genetics</subject><subject>Breast Neoplasms - metabolism</subject><subject>Breast Neoplasms - pathology</subject><subject>Cell Proliferation</subject><subject>Cells, Cultured</subject><subject>Collagen - metabolism</subject><subject>Epigenesis, Genetic</subject><subject>Epithelial-Mesenchymal Transition</subject><subject>Female</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Humans</subject><subject>Hydroxylation</subject><subject>Pluripotent Stem Cells - metabolism</subject><subject>Pluripotent Stem Cells - pathology</subject><subject>Prolyl Hydroxylases - genetics</subject><subject>Prolyl Hydroxylases - metabolism</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNo9kctu3iAQhVHUKPlzeYRWLLtxCsYYexm5uUm5KUrWaGzPn1JhcMGO4ifp6xYnaRASQvOdMzCHkK-cnXAuqx-MsSqThcpPmtPbjFdZzhTbIRsuRZWpopBfyOaT2ScHMf5OV8mZ3CP7grMybbkhfxtvLTyjo_fB28XSy6UP_nWxMBnvsp84ouvRTfQGJ2i9NR29xzDNoX0D6IV_weAiPRtNMsEp1R9w8D1a454puD4JI7ru1zKApY8BXDRvQpM62jmY0U-r_Uo24DoMtEFr4xHZ3YKNePxxHpKn87PH5jK7vru4ak6vs64o2ZQ-DapXabVFX3EsVFvzVtUAWJdKdYUooSwZSgCZ11gxgbDtU40hsjLnXByS7---Y_B_ZoyTHkzs0gvAoZ-jznORcyHqYkXlO9oFH2PArR6DGSAsmjO9ZqLXeet13jplonml10yS7ttHi7kdsP9U_Q9B_AOJYorv</recordid><startdate>20190701</startdate><enddate>20190701</enddate><creator>D'Aniello, Cristina</creator><creator>Cermola, Federica</creator><creator>Palamidessi, Andrea</creator><creator>Wanderlingh, Luca G</creator><creator>Gagliardi, Miriam</creator><creator>Migliaccio, Agnese</creator><creator>Varrone, Francesca</creator><creator>Casalino, Laura</creator><creator>Matarazzo, Maria R</creator><creator>De Cesare, Dario</creator><creator>Scita, Giorgio</creator><creator>Patriarca, Eduardo J</creator><creator>Minchiotti, Gabriella</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-7984-1889</orcidid><orcidid>https://orcid.org/0000-0003-0225-9043</orcidid><orcidid>https://orcid.org/0000-0002-6301-7534</orcidid><orcidid>https://orcid.org/0000-0003-0156-3705</orcidid></search><sort><creationdate>20190701</creationdate><title>Collagen Prolyl Hydroxylation-Dependent Metabolic Perturbation Governs Epigenetic Remodeling and Mesenchymal Transition in Pluripotent and Cancer Cells</title><author>D'Aniello, Cristina ; Cermola, Federica ; Palamidessi, Andrea ; Wanderlingh, Luca G ; Gagliardi, Miriam ; Migliaccio, Agnese ; Varrone, Francesca ; Casalino, Laura ; Matarazzo, Maria R ; De Cesare, Dario ; Scita, Giorgio ; Patriarca, Eduardo J ; Minchiotti, Gabriella</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c460t-20a7d7777b4d81e47b91b79aae9677c436a660e5aa529e803eafde960ee062113</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Breast Neoplasms - genetics</topic><topic>Breast Neoplasms - metabolism</topic><topic>Breast Neoplasms - pathology</topic><topic>Cell Proliferation</topic><topic>Cells, Cultured</topic><topic>Collagen - metabolism</topic><topic>Epigenesis, Genetic</topic><topic>Epithelial-Mesenchymal Transition</topic><topic>Female</topic><topic>Gene Expression Regulation, Neoplastic</topic><topic>Humans</topic><topic>Hydroxylation</topic><topic>Pluripotent Stem Cells - metabolism</topic><topic>Pluripotent Stem Cells - pathology</topic><topic>Prolyl Hydroxylases - genetics</topic><topic>Prolyl Hydroxylases - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>D'Aniello, Cristina</creatorcontrib><creatorcontrib>Cermola, Federica</creatorcontrib><creatorcontrib>Palamidessi, Andrea</creatorcontrib><creatorcontrib>Wanderlingh, Luca G</creatorcontrib><creatorcontrib>Gagliardi, Miriam</creatorcontrib><creatorcontrib>Migliaccio, Agnese</creatorcontrib><creatorcontrib>Varrone, Francesca</creatorcontrib><creatorcontrib>Casalino, Laura</creatorcontrib><creatorcontrib>Matarazzo, Maria R</creatorcontrib><creatorcontrib>De Cesare, Dario</creatorcontrib><creatorcontrib>Scita, Giorgio</creatorcontrib><creatorcontrib>Patriarca, Eduardo J</creatorcontrib><creatorcontrib>Minchiotti, Gabriella</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>D'Aniello, Cristina</au><au>Cermola, Federica</au><au>Palamidessi, Andrea</au><au>Wanderlingh, Luca G</au><au>Gagliardi, Miriam</au><au>Migliaccio, Agnese</au><au>Varrone, Francesca</au><au>Casalino, Laura</au><au>Matarazzo, Maria R</au><au>De Cesare, Dario</au><au>Scita, Giorgio</au><au>Patriarca, Eduardo J</au><au>Minchiotti, Gabriella</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Collagen Prolyl Hydroxylation-Dependent Metabolic Perturbation Governs Epigenetic Remodeling and Mesenchymal Transition in Pluripotent and Cancer Cells</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2019-07-01</date><risdate>2019</risdate><volume>79</volume><issue>13</issue><spage>3235</spage><epage>3250</epage><pages>3235-3250</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><abstract>Collagen prolyl hydroxylation (CPH), which is catalyzed by prolyl 4-hydroxylase (P4H), is the most prevalent posttranslational modification in humans and requires vitamin C (VitC). Here, we demonstrate that CPH acts as an epigenetic modulator of cell plasticity. Increased CPH induced global DNA/histone methylation in pluripotent stem and tumor cells and promoted cell state transition (CST). Interfering with CPH by either genetic ablation of P4H subunit alpha-2 (P4HA2) or pharmacologic treatment reverted epigenetic changes and antagonized CST. Mechanistically, we suggest that CPH modifies the epigenetic landscape by reducing VitC for DNA and histone demethylases. Repurposed drugs targeting CPH-mediated metabolic perturbation, such as the antiasthmatic budesonide, blocked metastatic dissemination of breast cancer cells
by preventing mesenchymal transition. Our study provides mechanistic insights into how metabolic cues and epigenetic factors integrate to control CST and paves the way for the development of novel antimetastatic strategies. SIGNIFICANCE: A phenotype-based high-throughput screening reveals unforeseen metabolic control of cell plasticity and identifies budesonide as a drug candidate for metastatic cancer.
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| ispartof | Cancer research (Chicago, Ill.), 2019-07, Vol.79 (13), p.3235-3250 |
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| subjects | Breast Neoplasms - genetics Breast Neoplasms - metabolism Breast Neoplasms - pathology Cell Proliferation Cells, Cultured Collagen - metabolism Epigenesis, Genetic Epithelial-Mesenchymal Transition Female Gene Expression Regulation, Neoplastic Humans Hydroxylation Pluripotent Stem Cells - metabolism Pluripotent Stem Cells - pathology Prolyl Hydroxylases - genetics Prolyl Hydroxylases - metabolism |
| title | Collagen Prolyl Hydroxylation-Dependent Metabolic Perturbation Governs Epigenetic Remodeling and Mesenchymal Transition in Pluripotent and Cancer Cells |
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