Downregulation of SREBP inhibits tumor growth and initiation by altering cellular metabolism in colon cancer
Sterol regulatory element-binding proteins (SREBPs) belong to a family of transcription factors that regulate the expression of genes required for the synthesis of fatty acids and cholesterol. Three SREBP isoforms, SREBP1a, SREBP1c, and SREBP2, have been identified in mammalian cells. SREBP1a and SR...
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| Veröffentlicht in: | Cell death & disease 2018-02, Vol.9 (3), p.265-14, Article 265 |
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| description | Sterol regulatory element-binding proteins (SREBPs) belong to a family of transcription factors that regulate the expression of genes required for the synthesis of fatty acids and cholesterol. Three SREBP isoforms, SREBP1a, SREBP1c, and SREBP2, have been identified in mammalian cells. SREBP1a and SREBP1c are derived from a single gene through the use of alternative transcription start sites. Here we investigated the role of SREBP-mediated lipogenesis in regulating tumor growth and initiation in colon cancer. Knockdown of either SREBP1 or SREBP2 decreased levels of fatty acids as a result of decreased expression of SREBP target genes required for lipid biosynthesis in colon cancer cells. Bioenergetic analysis revealed that silencing SREBP1 or SREBP2 expression reduced the mitochondrial respiration, glycolysis, as well as fatty acid oxidation indicating an alteration in cellular metabolism. Consequently, the rate of cell proliferation and the ability of cancer cells to form tumor spheroids in suspension culture were significantly decreased. Similar results were obtained in colon cancer cells in which the proteolytic activation of SREBP was blocked. Importantly, knockdown of either SREBP1 or SREBP2 inhibited xenograft tumor growth
in vivo
and decreased the expression of genes associated with cancer stem cells. Taken together, our findings establish the molecular basis of SREBP-dependent metabolic regulation and provide a rationale for targeting lipid biosynthesis as a promising approach in colon cancer treatment. |
| doi_str_mv | 10.1038/s41419-018-0330-6 |
| format | Article |
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in vivo
and decreased the expression of genes associated with cancer stem cells. Taken together, our findings establish the molecular basis of SREBP-dependent metabolic regulation and provide a rationale for targeting lipid biosynthesis as a promising approach in colon cancer treatment.</description><identifier>ISSN: 2041-4889</identifier><identifier>EISSN: 2041-4889</identifier><identifier>DOI: 10.1038/s41419-018-0330-6</identifier><identifier>PMID: 29449559</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/1 ; 13/89 ; 38 ; 38/77 ; 96 ; 96/106 ; Animals ; Antibodies ; Biochemistry ; Biomedical and Life Sciences ; Biosynthesis ; Cell Biology ; Cell Culture ; Cell Proliferation ; Cholesterol ; Colon cancer ; Colonic Neoplasms - genetics ; Colonic Neoplasms - metabolism ; Colonic Neoplasms - pathology ; Colorectal cancer ; Down-Regulation ; Electron transport ; Energy Metabolism ; Fatty acids ; Female ; Gene Expression Regulation, Neoplastic ; Gene regulation ; Glycolysis ; HCT116 Cells ; Humans ; Immunology ; Isoforms ; Life Sciences ; Lipogenesis ; Male ; Mammalian cells ; Metabolism ; Mice, Inbred NOD ; Mice, SCID ; Mitochondria ; Neoplastic Stem Cells - metabolism ; Neoplastic Stem Cells - pathology ; Oxidation ; Proteolysis ; Regulatory sequences ; Signal Transduction ; Spheroids ; Spheroids, Cellular ; Stem cells ; Sterol Regulatory Element Binding Protein 1 - genetics ; Sterol Regulatory Element Binding Protein 1 - metabolism ; Sterol Regulatory Element Binding Protein 2 - genetics ; Sterol Regulatory Element Binding Protein 2 - metabolism ; Sterol regulatory element-binding protein ; Suspension culture ; Transcription factors ; Tumor Burden ; Xenografts</subject><ispartof>Cell death & disease, 2018-02, Vol.9 (3), p.265-14, Article 265</ispartof><rights>The Author(s) 2018</rights><rights>2018. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). 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Mark</creatorcontrib><creatorcontrib>Gao, Tianyan</creatorcontrib><title>Downregulation of SREBP inhibits tumor growth and initiation by altering cellular metabolism in colon cancer</title><title>Cell death & disease</title><addtitle>Cell Death Dis</addtitle><addtitle>Cell Death Dis</addtitle><description>Sterol regulatory element-binding proteins (SREBPs) belong to a family of transcription factors that regulate the expression of genes required for the synthesis of fatty acids and cholesterol. Three SREBP isoforms, SREBP1a, SREBP1c, and SREBP2, have been identified in mammalian cells. SREBP1a and SREBP1c are derived from a single gene through the use of alternative transcription start sites. Here we investigated the role of SREBP-mediated lipogenesis in regulating tumor growth and initiation in colon cancer. Knockdown of either SREBP1 or SREBP2 decreased levels of fatty acids as a result of decreased expression of SREBP target genes required for lipid biosynthesis in colon cancer cells. Bioenergetic analysis revealed that silencing SREBP1 or SREBP2 expression reduced the mitochondrial respiration, glycolysis, as well as fatty acid oxidation indicating an alteration in cellular metabolism. Consequently, the rate of cell proliferation and the ability of cancer cells to form tumor spheroids in suspension culture were significantly decreased. Similar results were obtained in colon cancer cells in which the proteolytic activation of SREBP was blocked. Importantly, knockdown of either SREBP1 or SREBP2 inhibited xenograft tumor growth
in vivo
and decreased the expression of genes associated with cancer stem cells. Taken together, our findings establish the molecular basis of SREBP-dependent metabolic regulation and provide a rationale for targeting lipid biosynthesis as a promising approach in colon cancer treatment.</description><subject>13/1</subject><subject>13/89</subject><subject>38</subject><subject>38/77</subject><subject>96</subject><subject>96/106</subject><subject>Animals</subject><subject>Antibodies</subject><subject>Biochemistry</subject><subject>Biomedical and Life Sciences</subject><subject>Biosynthesis</subject><subject>Cell Biology</subject><subject>Cell Culture</subject><subject>Cell Proliferation</subject><subject>Cholesterol</subject><subject>Colon cancer</subject><subject>Colonic Neoplasms - genetics</subject><subject>Colonic Neoplasms - metabolism</subject><subject>Colonic Neoplasms - pathology</subject><subject>Colorectal cancer</subject><subject>Down-Regulation</subject><subject>Electron transport</subject><subject>Energy Metabolism</subject><subject>Fatty acids</subject><subject>Female</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Gene regulation</subject><subject>Glycolysis</subject><subject>HCT116 Cells</subject><subject>Humans</subject><subject>Immunology</subject><subject>Isoforms</subject><subject>Life Sciences</subject><subject>Lipogenesis</subject><subject>Male</subject><subject>Mammalian cells</subject><subject>Metabolism</subject><subject>Mice, Inbred NOD</subject><subject>Mice, SCID</subject><subject>Mitochondria</subject><subject>Neoplastic Stem Cells - metabolism</subject><subject>Neoplastic Stem Cells - pathology</subject><subject>Oxidation</subject><subject>Proteolysis</subject><subject>Regulatory sequences</subject><subject>Signal Transduction</subject><subject>Spheroids</subject><subject>Spheroids, Cellular</subject><subject>Stem cells</subject><subject>Sterol Regulatory Element Binding Protein 1 - genetics</subject><subject>Sterol Regulatory Element Binding Protein 1 - metabolism</subject><subject>Sterol Regulatory Element Binding Protein 2 - genetics</subject><subject>Sterol Regulatory Element Binding Protein 2 - metabolism</subject><subject>Sterol regulatory element-binding protein</subject><subject>Suspension culture</subject><subject>Transcription factors</subject><subject>Tumor Burden</subject><subject>Xenografts</subject><issn>2041-4889</issn><issn>2041-4889</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNp1kU9PHSEUxYmpUWP9AN0YEjfdTAsMwxs2TazaP4mJxrZrwjDMexgGXoHR-O29k1Frm5QNJPd3z-Xcg9A7Sj5QUrcfM6ecyorQtiJ1TSqxgw4Y4bTibSvfvHrvo6OcbwkcwFgj9tA-k5zLppEHyJ_H-5DsevK6uBhwHPCPm4vP19iFjetcybhMY0x4neJ92WAdeqi44ha6e8DaF5tcWGNjvQeVhEdbdBe9yyOg2EQPoNHB2PQW7Q7aZ3v0dB-iX18ufp59qy6vvn4_O72sDBeiVCtKGZddy3pRa9nbfhCc9lJLIwY6aKM7Y7QU4JxL0nGocGZWlLd6IJQ2tj5Enxbd7dSNtjc2lKS92iY36vSgonbq70pwG7WOd6pp67ohFATePwmk-HuyuajR5dmgDjZOWTHYJeGEshrQk3_Q2zilAPZmivEV7JoARRfKpJhzssPLZyhRc5xqiVOBKTXnpAT0HL928dLxHB4AbAHydk7Apj-j_6_6CA0trHQ</recordid><startdate>20180215</startdate><enddate>20180215</enddate><creator>Wen, Yang-An</creator><creator>Xiong, Xiaopeng</creator><creator>Zaytseva, Yekaterina Y.</creator><creator>Napier, Dana L.</creator><creator>Vallee, Emma</creator><creator>Li, Austin T.</creator><creator>Wang, Chi</creator><creator>Weiss, Heidi L.</creator><creator>Evers, B. 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Mark</au><au>Gao, Tianyan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Downregulation of SREBP inhibits tumor growth and initiation by altering cellular metabolism in colon cancer</atitle><jtitle>Cell death & disease</jtitle><stitle>Cell Death Dis</stitle><addtitle>Cell Death Dis</addtitle><date>2018-02-15</date><risdate>2018</risdate><volume>9</volume><issue>3</issue><spage>265</spage><epage>14</epage><pages>265-14</pages><artnum>265</artnum><issn>2041-4889</issn><eissn>2041-4889</eissn><abstract>Sterol regulatory element-binding proteins (SREBPs) belong to a family of transcription factors that regulate the expression of genes required for the synthesis of fatty acids and cholesterol. Three SREBP isoforms, SREBP1a, SREBP1c, and SREBP2, have been identified in mammalian cells. SREBP1a and SREBP1c are derived from a single gene through the use of alternative transcription start sites. Here we investigated the role of SREBP-mediated lipogenesis in regulating tumor growth and initiation in colon cancer. Knockdown of either SREBP1 or SREBP2 decreased levels of fatty acids as a result of decreased expression of SREBP target genes required for lipid biosynthesis in colon cancer cells. Bioenergetic analysis revealed that silencing SREBP1 or SREBP2 expression reduced the mitochondrial respiration, glycolysis, as well as fatty acid oxidation indicating an alteration in cellular metabolism. Consequently, the rate of cell proliferation and the ability of cancer cells to form tumor spheroids in suspension culture were significantly decreased. Similar results were obtained in colon cancer cells in which the proteolytic activation of SREBP was blocked. Importantly, knockdown of either SREBP1 or SREBP2 inhibited xenograft tumor growth
in vivo
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| subjects | 13/1 13/89 38 38/77 96 96/106 Animals Antibodies Biochemistry Biomedical and Life Sciences Biosynthesis Cell Biology Cell Culture Cell Proliferation Cholesterol Colon cancer Colonic Neoplasms - genetics Colonic Neoplasms - metabolism Colonic Neoplasms - pathology Colorectal cancer Down-Regulation Electron transport Energy Metabolism Fatty acids Female Gene Expression Regulation, Neoplastic Gene regulation Glycolysis HCT116 Cells Humans Immunology Isoforms Life Sciences Lipogenesis Male Mammalian cells Metabolism Mice, Inbred NOD Mice, SCID Mitochondria Neoplastic Stem Cells - metabolism Neoplastic Stem Cells - pathology Oxidation Proteolysis Regulatory sequences Signal Transduction Spheroids Spheroids, Cellular Stem cells Sterol Regulatory Element Binding Protein 1 - genetics Sterol Regulatory Element Binding Protein 1 - metabolism Sterol Regulatory Element Binding Protein 2 - genetics Sterol Regulatory Element Binding Protein 2 - metabolism Sterol regulatory element-binding protein Suspension culture Transcription factors Tumor Burden Xenografts |
| title | Downregulation of SREBP inhibits tumor growth and initiation by altering cellular metabolism in colon cancer |
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