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Novel Histone Demethylase LSD1 Inhibitors Selectively Target Cancer Cells with Pluripotent Stem Cell Properties
Histone modification determines epigenetic patterns of gene expression with methylation of histone H3 at lysine 4 (H3K4) often associated with active promoters. LSD1/KDM1 is a histone demethylase that suppresses gene expression by converting dimethylated H3K4 to mono- and unmethylated H3K4. LSD1 is...
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| Published in: | Cancer research (Chicago, Ill.) Ill.), 2011-12, Vol.71 (23), p.7238-7249 |
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| container_issue | 23 |
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| container_title | Cancer research (Chicago, Ill.) |
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| creator | JINGWANG FEILU HUI ZHANG QI REN HONG SUN ZHENGSHUANG XU RONGFENG LAN YUQING LIU WARD, David JUNMIN OUAN TAO YE |
| description | Histone modification determines epigenetic patterns of gene expression with methylation of histone H3 at lysine 4 (H3K4) often associated with active promoters. LSD1/KDM1 is a histone demethylase that suppresses gene expression by converting dimethylated H3K4 to mono- and unmethylated H3K4. LSD1 is essential for metazoan development, but its pathophysiologic functions in cancer remain mainly uncharacterized. In this study, we developed specific bioactive small inhibitors of LSD1 that enhance H3K4 methylation and derepress epigenetically suppressed genes in vivo. Strikingly, these compounds inhibited the proliferation of pluripotent cancer cells including teratocarcinoma, embryonic carcinoma, and seminoma or embryonic stem cells that express the stem cell markers Oct4 and Sox2 while displaying minimum growth-inhibitory effects on non-pluripotent cancer or normal somatic cells. RNA interference-mediated knockdown of LSD1 expression phenocopied these effects, confirming the specificity of small molecules and further establishing the high degree of sensitivity and selectivity of pluripotent cancer cells to LSD1 ablation. In support of these results, we found that LSD1 protein level is highly elevated in pluripotent cancer cells and in human testicular seminoma tissues that express Oct4. Using these novel chemical inhibitors as probes, our findings establish LSD1 and histone H3K4 methylation as essential cancer-selective epigenetic targets in cancer cells that have pluripotent stem cell properties. |
| doi_str_mv | 10.1158/0008-5472.CAN-11-0896 |
| format | article |
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LSD1/KDM1 is a histone demethylase that suppresses gene expression by converting dimethylated H3K4 to mono- and unmethylated H3K4. LSD1 is essential for metazoan development, but its pathophysiologic functions in cancer remain mainly uncharacterized. In this study, we developed specific bioactive small inhibitors of LSD1 that enhance H3K4 methylation and derepress epigenetically suppressed genes in vivo. Strikingly, these compounds inhibited the proliferation of pluripotent cancer cells including teratocarcinoma, embryonic carcinoma, and seminoma or embryonic stem cells that express the stem cell markers Oct4 and Sox2 while displaying minimum growth-inhibitory effects on non-pluripotent cancer or normal somatic cells. RNA interference-mediated knockdown of LSD1 expression phenocopied these effects, confirming the specificity of small molecules and further establishing the high degree of sensitivity and selectivity of pluripotent cancer cells to LSD1 ablation. In support of these results, we found that LSD1 protein level is highly elevated in pluripotent cancer cells and in human testicular seminoma tissues that express Oct4. Using these novel chemical inhibitors as probes, our findings establish LSD1 and histone H3K4 methylation as essential cancer-selective epigenetic targets in cancer cells that have pluripotent stem cell properties.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>DOI: 10.1158/0008-5472.CAN-11-0896</identifier><identifier>PMID: 21975933</identifier><identifier>CODEN: CNREA8</identifier><language>eng</language><publisher>Philadelphia, PA: American Association for Cancer Research</publisher><subject>Animals ; Antineoplastic agents ; Antineoplastic Agents - pharmacology ; Biological and medical sciences ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Embryonic Stem Cells - enzymology ; Embryonic Stem Cells - metabolism ; Epigenomics - methods ; HEK293 Cells ; HeLa Cells ; Histone Demethylases - antagonists & inhibitors ; Histone Demethylases - biosynthesis ; Histone Demethylases - genetics ; Histones - metabolism ; Humans ; Medical sciences ; Metazoa ; Methylation - drug effects ; Mice ; Neoplasms - drug therapy ; Neoplasms - enzymology ; Neoplasms - metabolism ; Neoplasms - pathology ; NIH 3T3 Cells ; Octamer Transcription Factor-3 - biosynthesis ; Octamer Transcription Factor-3 - genetics ; Pharmacology. Drug treatments ; Pluripotent Stem Cells - drug effects ; Pluripotent Stem Cells - enzymology ; Pluripotent Stem Cells - metabolism ; Pluripotent Stem Cells - pathology ; RNA Interference ; Sensitivity and Specificity ; SOXB1 Transcription Factors - biosynthesis ; SOXB1 Transcription Factors - genetics ; Tumors</subject><ispartof>Cancer research (Chicago, Ill.), 2011-12, Vol.71 (23), p.7238-7249</ispartof><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c524t-a75ba07f142ff6a8d63271aaf8c3de164f6032fd091f9ab97275738d4670b8ce3</citedby><cites>FETCH-LOGICAL-c524t-a75ba07f142ff6a8d63271aaf8c3de164f6032fd091f9ab97275738d4670b8ce3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,786,790,891,27957,27958</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=25250482$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21975933$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>JINGWANG</creatorcontrib><creatorcontrib>FEILU</creatorcontrib><creatorcontrib>HUI ZHANG</creatorcontrib><creatorcontrib>QI REN</creatorcontrib><creatorcontrib>HONG SUN</creatorcontrib><creatorcontrib>ZHENGSHUANG XU</creatorcontrib><creatorcontrib>RONGFENG LAN</creatorcontrib><creatorcontrib>YUQING LIU</creatorcontrib><creatorcontrib>WARD, David</creatorcontrib><creatorcontrib>JUNMIN OUAN</creatorcontrib><creatorcontrib>TAO YE</creatorcontrib><title>Novel Histone Demethylase LSD1 Inhibitors Selectively Target Cancer Cells with Pluripotent Stem Cell Properties</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>Histone modification determines epigenetic patterns of gene expression with methylation of histone H3 at lysine 4 (H3K4) often associated with active promoters. LSD1/KDM1 is a histone demethylase that suppresses gene expression by converting dimethylated H3K4 to mono- and unmethylated H3K4. LSD1 is essential for metazoan development, but its pathophysiologic functions in cancer remain mainly uncharacterized. In this study, we developed specific bioactive small inhibitors of LSD1 that enhance H3K4 methylation and derepress epigenetically suppressed genes in vivo. Strikingly, these compounds inhibited the proliferation of pluripotent cancer cells including teratocarcinoma, embryonic carcinoma, and seminoma or embryonic stem cells that express the stem cell markers Oct4 and Sox2 while displaying minimum growth-inhibitory effects on non-pluripotent cancer or normal somatic cells. RNA interference-mediated knockdown of LSD1 expression phenocopied these effects, confirming the specificity of small molecules and further establishing the high degree of sensitivity and selectivity of pluripotent cancer cells to LSD1 ablation. In support of these results, we found that LSD1 protein level is highly elevated in pluripotent cancer cells and in human testicular seminoma tissues that express Oct4. Using these novel chemical inhibitors as probes, our findings establish LSD1 and histone H3K4 methylation as essential cancer-selective epigenetic targets in cancer cells that have pluripotent stem cell properties.</description><subject>Animals</subject><subject>Antineoplastic agents</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Embryonic Stem Cells - enzymology</subject><subject>Embryonic Stem Cells - metabolism</subject><subject>Epigenomics - methods</subject><subject>HEK293 Cells</subject><subject>HeLa Cells</subject><subject>Histone Demethylases - antagonists & inhibitors</subject><subject>Histone Demethylases - biosynthesis</subject><subject>Histone Demethylases - genetics</subject><subject>Histones - metabolism</subject><subject>Humans</subject><subject>Medical sciences</subject><subject>Metazoa</subject><subject>Methylation - drug effects</subject><subject>Mice</subject><subject>Neoplasms - drug therapy</subject><subject>Neoplasms - enzymology</subject><subject>Neoplasms - metabolism</subject><subject>Neoplasms - pathology</subject><subject>NIH 3T3 Cells</subject><subject>Octamer Transcription Factor-3 - biosynthesis</subject><subject>Octamer Transcription Factor-3 - genetics</subject><subject>Pharmacology. Drug treatments</subject><subject>Pluripotent Stem Cells - drug effects</subject><subject>Pluripotent Stem Cells - enzymology</subject><subject>Pluripotent Stem Cells - metabolism</subject><subject>Pluripotent Stem Cells - pathology</subject><subject>RNA Interference</subject><subject>Sensitivity and Specificity</subject><subject>SOXB1 Transcription Factors - biosynthesis</subject><subject>SOXB1 Transcription Factors - genetics</subject><subject>Tumors</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><recordid>eNpVkV1vFCEUhonR2LX6EzTcmF5N5WMYmBuTZmptk01tsvWaMMyhi5kZVmBr9t-XteuqVwTOc14OPAi9p-ScUqE-EUJUJWrJzruL24rSiqi2eYEWVHBVyboWL9HiyJygNyn9KFtBiXiNThhtpWg5X6BwGx5hxNc-5TADvoQJ8no3mgR4ubqk-GZe-97nEBNewQg2-4Lv8L2JD5BxZ2YLEXcwjgn_8nmN78Zt9JuQYc54lWH6XcN3MWwgZg_pLXrlzJjg3WE9Rd-vvtx319Xy29eb7mJZWcHqXBkpekOkozVzrjFqaDiT1BinLB-ANrVrCGduIC11relbyaSQXA11I0mvLPBT9Pk5d7PtJxhsmSeaUW-in0zc6WC8_r8y-7V-CI-aM6ZaQkvA2SEghp9bSFlPPtnyGDND2CbdsqYlhNZNIcUzaWNIKYI73kKJ3rvSew9670EXV-VI712Vvg__jnjs-iOnAB8PgEnWjC6W3_bpLyeYILVi_AneSp7v</recordid><startdate>20111201</startdate><enddate>20111201</enddate><creator>JINGWANG</creator><creator>FEILU</creator><creator>HUI ZHANG</creator><creator>QI REN</creator><creator>HONG SUN</creator><creator>ZHENGSHUANG XU</creator><creator>RONGFENG LAN</creator><creator>YUQING LIU</creator><creator>WARD, David</creator><creator>JUNMIN OUAN</creator><creator>TAO YE</creator><general>American Association for Cancer Research</general><scope>IQODW</scope><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>7TM</scope><scope>5PM</scope></search><sort><creationdate>20111201</creationdate><title>Novel Histone Demethylase LSD1 Inhibitors Selectively Target Cancer Cells with Pluripotent Stem Cell Properties</title><author>JINGWANG ; FEILU ; HUI ZHANG ; QI REN ; HONG SUN ; ZHENGSHUANG XU ; RONGFENG LAN ; YUQING LIU ; WARD, David ; JUNMIN OUAN ; TAO YE</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c524t-a75ba07f142ff6a8d63271aaf8c3de164f6032fd091f9ab97275738d4670b8ce3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Animals</topic><topic>Antineoplastic agents</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Embryonic Stem Cells - enzymology</topic><topic>Embryonic Stem Cells - metabolism</topic><topic>Epigenomics - methods</topic><topic>HEK293 Cells</topic><topic>HeLa Cells</topic><topic>Histone Demethylases - antagonists & inhibitors</topic><topic>Histone Demethylases - biosynthesis</topic><topic>Histone Demethylases - genetics</topic><topic>Histones - metabolism</topic><topic>Humans</topic><topic>Medical sciences</topic><topic>Metazoa</topic><topic>Methylation - drug effects</topic><topic>Mice</topic><topic>Neoplasms - drug therapy</topic><topic>Neoplasms - enzymology</topic><topic>Neoplasms - metabolism</topic><topic>Neoplasms - pathology</topic><topic>NIH 3T3 Cells</topic><topic>Octamer Transcription Factor-3 - biosynthesis</topic><topic>Octamer Transcription Factor-3 - genetics</topic><topic>Pharmacology. Drug treatments</topic><topic>Pluripotent Stem Cells - drug effects</topic><topic>Pluripotent Stem Cells - enzymology</topic><topic>Pluripotent Stem Cells - metabolism</topic><topic>Pluripotent Stem Cells - pathology</topic><topic>RNA Interference</topic><topic>Sensitivity and Specificity</topic><topic>SOXB1 Transcription Factors - biosynthesis</topic><topic>SOXB1 Transcription Factors - genetics</topic><topic>Tumors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>JINGWANG</creatorcontrib><creatorcontrib>FEILU</creatorcontrib><creatorcontrib>HUI ZHANG</creatorcontrib><creatorcontrib>QI REN</creatorcontrib><creatorcontrib>HONG SUN</creatorcontrib><creatorcontrib>ZHENGSHUANG XU</creatorcontrib><creatorcontrib>RONGFENG LAN</creatorcontrib><creatorcontrib>YUQING LIU</creatorcontrib><creatorcontrib>WARD, David</creatorcontrib><creatorcontrib>JUNMIN OUAN</creatorcontrib><creatorcontrib>TAO YE</creatorcontrib><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Nucleic Acids Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Cancer research (Chicago, Ill.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>JINGWANG</au><au>FEILU</au><au>HUI ZHANG</au><au>QI REN</au><au>HONG SUN</au><au>ZHENGSHUANG XU</au><au>RONGFENG LAN</au><au>YUQING LIU</au><au>WARD, David</au><au>JUNMIN OUAN</au><au>TAO YE</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Novel Histone Demethylase LSD1 Inhibitors Selectively Target Cancer Cells with Pluripotent Stem Cell Properties</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2011-12-01</date><risdate>2011</risdate><volume>71</volume><issue>23</issue><spage>7238</spage><epage>7249</epage><pages>7238-7249</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><coden>CNREA8</coden><notes>ObjectType-Article-2</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-1</notes><notes>content type line 23</notes><notes>these authors made equal contributions</notes><abstract>Histone modification determines epigenetic patterns of gene expression with methylation of histone H3 at lysine 4 (H3K4) often associated with active promoters. LSD1/KDM1 is a histone demethylase that suppresses gene expression by converting dimethylated H3K4 to mono- and unmethylated H3K4. LSD1 is essential for metazoan development, but its pathophysiologic functions in cancer remain mainly uncharacterized. In this study, we developed specific bioactive small inhibitors of LSD1 that enhance H3K4 methylation and derepress epigenetically suppressed genes in vivo. Strikingly, these compounds inhibited the proliferation of pluripotent cancer cells including teratocarcinoma, embryonic carcinoma, and seminoma or embryonic stem cells that express the stem cell markers Oct4 and Sox2 while displaying minimum growth-inhibitory effects on non-pluripotent cancer or normal somatic cells. RNA interference-mediated knockdown of LSD1 expression phenocopied these effects, confirming the specificity of small molecules and further establishing the high degree of sensitivity and selectivity of pluripotent cancer cells to LSD1 ablation. In support of these results, we found that LSD1 protein level is highly elevated in pluripotent cancer cells and in human testicular seminoma tissues that express Oct4. Using these novel chemical inhibitors as probes, our findings establish LSD1 and histone H3K4 methylation as essential cancer-selective epigenetic targets in cancer cells that have pluripotent stem cell properties.</abstract><cop>Philadelphia, PA</cop><pub>American Association for Cancer Research</pub><pmid>21975933</pmid><doi>10.1158/0008-5472.CAN-11-0896</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Cancer research (Chicago, Ill.), 2011-12, Vol.71 (23), p.7238-7249 |
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| subjects | Animals Antineoplastic agents Antineoplastic Agents - pharmacology Biological and medical sciences Cell Line, Tumor Cell Proliferation - drug effects Embryonic Stem Cells - enzymology Embryonic Stem Cells - metabolism Epigenomics - methods HEK293 Cells HeLa Cells Histone Demethylases - antagonists & inhibitors Histone Demethylases - biosynthesis Histone Demethylases - genetics Histones - metabolism Humans Medical sciences Metazoa Methylation - drug effects Mice Neoplasms - drug therapy Neoplasms - enzymology Neoplasms - metabolism Neoplasms - pathology NIH 3T3 Cells Octamer Transcription Factor-3 - biosynthesis Octamer Transcription Factor-3 - genetics Pharmacology. Drug treatments Pluripotent Stem Cells - drug effects Pluripotent Stem Cells - enzymology Pluripotent Stem Cells - metabolism Pluripotent Stem Cells - pathology RNA Interference Sensitivity and Specificity SOXB1 Transcription Factors - biosynthesis SOXB1 Transcription Factors - genetics Tumors |
| title | Novel Histone Demethylase LSD1 Inhibitors Selectively Target Cancer Cells with Pluripotent Stem Cell Properties |
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