Targeting MYC dependence in cancer by inhibiting BET bromodomains
The MYC transcription factor is a master regulator of diverse cellular functions and has been long considered a compelling therapeutic target because of its role in a range of human malignancies. However, pharmacologic inhibition of MYC function has proven challenging because of both the diverse mec...
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| Veröffentlicht in: | Proceedings of the National Academy of Sciences - PNAS 2011-10, Vol.108 (40), p.16669-16674 |
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| creator | Mertz, Jennifer A Conery, Andrew R Bryant, Barbara M Sandy, Peter Balasubramanian, Srividya Mele, Deanna A Bergeron, Louise Sims, Robert J., III |
| description | The MYC transcription factor is a master regulator of diverse cellular functions and has been long considered a compelling therapeutic target because of its role in a range of human malignancies. However, pharmacologic inhibition of MYC function has proven challenging because of both the diverse mechanisms driving its aberrant expression and the challenge of disrupting protein–DNA interactions. Here, we demonstrate the rapid and potent abrogation of MYC gene transcription by representative small molecule inhibitors of the BET family of chromatin adaptors. MYC transcriptional suppression was observed in the context of the natural, chromosomally translocated, and amplified gene locus. Inhibition of BET bromodomain–promoter interactions and subsequent reduction of MYC transcript and protein levels resulted in G1 arrest and extensive apoptosis in a variety of leukemia and lymphoma cell lines. Exogenous expression of MYC from an artificial promoter that is resistant to BET regulation significantly protected cells from cell cycle arrest and growth suppression by BET inhibitors. MYC suppression was accompanied by deregulation of the MYC transcriptome, including potent reactivation of the p21 tumor suppressor. Treatment with a BET inhibitor resulted in significant antitumor activity in xenograft models of Burkitt's lymphoma and acute myeloid leukemia. These findings demonstrate that pharmacologic inhibition of MYC is achievable through targeting BET bromodomains. Such inhibitors may have clinical utility given the widespread pathogenetic role of MYC in cancer. |
| doi_str_mv | 10.1073/pnas.1108190108 |
| format | Article |
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However, pharmacologic inhibition of MYC function has proven challenging because of both the diverse mechanisms driving its aberrant expression and the challenge of disrupting protein–DNA interactions. Here, we demonstrate the rapid and potent abrogation of MYC gene transcription by representative small molecule inhibitors of the BET family of chromatin adaptors. MYC transcriptional suppression was observed in the context of the natural, chromosomally translocated, and amplified gene locus. Inhibition of BET bromodomain–promoter interactions and subsequent reduction of MYC transcript and protein levels resulted in G1 arrest and extensive apoptosis in a variety of leukemia and lymphoma cell lines. Exogenous expression of MYC from an artificial promoter that is resistant to BET regulation significantly protected cells from cell cycle arrest and growth suppression by BET inhibitors. MYC suppression was accompanied by deregulation of the MYC transcriptome, including potent reactivation of the p21 tumor suppressor. Treatment with a BET inhibitor resulted in significant antitumor activity in xenograft models of Burkitt's lymphoma and acute myeloid leukemia. These findings demonstrate that pharmacologic inhibition of MYC is achievable through targeting BET bromodomains. Such inhibitors may have clinical utility given the widespread pathogenetic role of MYC in cancer.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1108190108</identifier><identifier>PMID: 21949397</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>Animals ; anticarcinogenic activity ; Apoptosis ; Apoptosis - genetics ; Apoptosis - physiology ; Azepines - pharmacology ; Betting ; Biological Sciences ; Blotting, Western ; Burkitt Lymphoma - drug therapy ; Cancer ; Cell cycle ; Cell Cycle - physiology ; Cell Line, Tumor ; Cell lines ; Cell Proliferation - drug effects ; Chromatin ; Chromatin Immunoprecipitation ; chromosome translocation ; DNA-Binding Proteins - antagonists & inhibitors ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - metabolism ; Dose-Response Relationship, Drug ; Flow Cytometry ; Gene expression ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic - drug effects ; Gene Expression Regulation, Neoplastic - physiology ; Genes ; Genetic loci ; HeLa cells ; Humans ; Leukemia, Myeloid, Acute - drug therapy ; loci ; lymphoma ; Messenger RNA ; Mice ; Mice, Inbred NOD ; Mice, SCID ; myeloid leukemia ; Polymerase Chain Reaction ; Protein Structure, Tertiary - genetics ; Proteins ; RNA, Small Interfering - genetics ; transcription (genetics) ; transcription factors ; Transcription Factors - antagonists & inhibitors ; Transcription Factors - genetics ; Transcription Factors - metabolism ; transcriptome ; Triazoles - pharmacology ; Tumors ; Viability</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2011-10, Vol.108 (40), p.16669-16674</ispartof><rights>copyright © 1993-2008 National Academy of Sciences of the United States of America</rights><rights>Copyright National Academy of Sciences Oct 4, 2011</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c556t-3f488e4c6fba3b49bb12acb20caef84547352a9483ecaa46e8820a664cfe454a3</citedby><cites>FETCH-LOGICAL-c556t-3f488e4c6fba3b49bb12acb20caef84547352a9483ecaa46e8820a664cfe454a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/108/40.cover.gif</thumbnail><linktopdf>$$Uhttps://www.jstor.org/stable/pdf/41321759$$EPDF$$P50$$Gjstor$$H</linktopdf><linktohtml>$$Uhttps://www.jstor.org/stable/41321759$$EHTML$$P50$$Gjstor$$H</linktohtml><link.rule.ids>230,315,729,782,786,805,887,27931,27932,53798,53800,58024,58257</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21949397$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Mertz, Jennifer A</creatorcontrib><creatorcontrib>Conery, Andrew R</creatorcontrib><creatorcontrib>Bryant, Barbara M</creatorcontrib><creatorcontrib>Sandy, Peter</creatorcontrib><creatorcontrib>Balasubramanian, Srividya</creatorcontrib><creatorcontrib>Mele, Deanna A</creatorcontrib><creatorcontrib>Bergeron, Louise</creatorcontrib><creatorcontrib>Sims, Robert J., III</creatorcontrib><title>Targeting MYC dependence in cancer by inhibiting BET bromodomains</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>The MYC transcription factor is a master regulator of diverse cellular functions and has been long considered a compelling therapeutic target because of its role in a range of human malignancies. However, pharmacologic inhibition of MYC function has proven challenging because of both the diverse mechanisms driving its aberrant expression and the challenge of disrupting protein–DNA interactions. Here, we demonstrate the rapid and potent abrogation of MYC gene transcription by representative small molecule inhibitors of the BET family of chromatin adaptors. MYC transcriptional suppression was observed in the context of the natural, chromosomally translocated, and amplified gene locus. Inhibition of BET bromodomain–promoter interactions and subsequent reduction of MYC transcript and protein levels resulted in G1 arrest and extensive apoptosis in a variety of leukemia and lymphoma cell lines. Exogenous expression of MYC from an artificial promoter that is resistant to BET regulation significantly protected cells from cell cycle arrest and growth suppression by BET inhibitors. MYC suppression was accompanied by deregulation of the MYC transcriptome, including potent reactivation of the p21 tumor suppressor. Treatment with a BET inhibitor resulted in significant antitumor activity in xenograft models of Burkitt's lymphoma and acute myeloid leukemia. These findings demonstrate that pharmacologic inhibition of MYC is achievable through targeting BET bromodomains. Such inhibitors may have clinical utility given the widespread pathogenetic role of MYC in cancer.</description><subject>Animals</subject><subject>anticarcinogenic activity</subject><subject>Apoptosis</subject><subject>Apoptosis - genetics</subject><subject>Apoptosis - physiology</subject><subject>Azepines - pharmacology</subject><subject>Betting</subject><subject>Biological Sciences</subject><subject>Blotting, Western</subject><subject>Burkitt Lymphoma - drug therapy</subject><subject>Cancer</subject><subject>Cell cycle</subject><subject>Cell Cycle - physiology</subject><subject>Cell Line, Tumor</subject><subject>Cell lines</subject><subject>Cell Proliferation - drug effects</subject><subject>Chromatin</subject><subject>Chromatin Immunoprecipitation</subject><subject>chromosome translocation</subject><subject>DNA-Binding Proteins - antagonists & inhibitors</subject><subject>DNA-Binding Proteins - genetics</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Dose-Response Relationship, Drug</subject><subject>Flow Cytometry</subject><subject>Gene expression</subject><subject>Gene Expression Profiling</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Gene Expression Regulation, Neoplastic - physiology</subject><subject>Genes</subject><subject>Genetic loci</subject><subject>HeLa cells</subject><subject>Humans</subject><subject>Leukemia, Myeloid, Acute - drug therapy</subject><subject>loci</subject><subject>lymphoma</subject><subject>Messenger RNA</subject><subject>Mice</subject><subject>Mice, Inbred NOD</subject><subject>Mice, SCID</subject><subject>myeloid leukemia</subject><subject>Polymerase Chain Reaction</subject><subject>Protein Structure, Tertiary - genetics</subject><subject>Proteins</subject><subject>RNA, Small Interfering - genetics</subject><subject>transcription (genetics)</subject><subject>transcription factors</subject><subject>Transcription Factors - antagonists & inhibitors</subject><subject>Transcription Factors - genetics</subject><subject>Transcription Factors - metabolism</subject><subject>transcriptome</subject><subject>Triazoles - pharmacology</subject><subject>Tumors</subject><subject>Viability</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVkM1vEzEQxS1ERUPhzAlYcd92_LFe-4LURm2p1IoD6YGTNXa8qaPGDvYGqf89DgkpvYzHer95M3qEfKBwSqHnZ-uI5ZRSUFRDra_IhIKmrRQaXpMJAOtbJZg4Jm9LWQKA7hS8IceMaqG57ifkfIZ54ccQF83dz2kz92sf5z4634TYOKxNbuxT_TwEG_5iF5ezxua0SvO0whDLO3I04GPx7_fvCbm_upxNv7W3369vpue3res6ObZ8EEp54eRgkVuhraUMnWXg0A9KdKLnHUMtFPcOUUivFAOUUrjBVxX5Cfm6811v7MrPnY9jxkezzmGF-ckkDOalEsODWaTfhlOloVfV4MveIKdfG19Gs0ybHOvNRmkptRYUKnS2g1xOpWQ_HBZQMNvIzTZy8xx5nfj0_10H_l_GFWj2wHby2U4ZUS1l3VyRjztkWcaUD4ygnNG-2-qfd_qAyeAih2LufzCgAoD2UtOO_wGegpqX</recordid><startdate>20111004</startdate><enddate>20111004</enddate><creator>Mertz, Jennifer A</creator><creator>Conery, Andrew R</creator><creator>Bryant, Barbara M</creator><creator>Sandy, Peter</creator><creator>Balasubramanian, Srividya</creator><creator>Mele, Deanna A</creator><creator>Bergeron, Louise</creator><creator>Sims, Robert J., III</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>FBQ</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>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>5PM</scope></search><sort><creationdate>20111004</creationdate><title>Targeting MYC dependence in cancer by inhibiting BET bromodomains</title><author>Mertz, Jennifer A ; Conery, Andrew R ; Bryant, Barbara M ; Sandy, Peter ; Balasubramanian, Srividya ; Mele, Deanna A ; Bergeron, Louise ; Sims, Robert J., III</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c556t-3f488e4c6fba3b49bb12acb20caef84547352a9483ecaa46e8820a664cfe454a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Animals</topic><topic>anticarcinogenic activity</topic><topic>Apoptosis</topic><topic>Apoptosis - genetics</topic><topic>Apoptosis - physiology</topic><topic>Azepines - pharmacology</topic><topic>Betting</topic><topic>Biological Sciences</topic><topic>Blotting, Western</topic><topic>Burkitt Lymphoma - drug therapy</topic><topic>Cancer</topic><topic>Cell cycle</topic><topic>Cell Cycle - physiology</topic><topic>Cell Line, Tumor</topic><topic>Cell lines</topic><topic>Cell Proliferation - drug effects</topic><topic>Chromatin</topic><topic>Chromatin Immunoprecipitation</topic><topic>chromosome translocation</topic><topic>DNA-Binding Proteins - antagonists & inhibitors</topic><topic>DNA-Binding Proteins - genetics</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Dose-Response Relationship, Drug</topic><topic>Flow Cytometry</topic><topic>Gene expression</topic><topic>Gene Expression Profiling</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>Gene Expression Regulation, Neoplastic - physiology</topic><topic>Genes</topic><topic>Genetic loci</topic><topic>HeLa cells</topic><topic>Humans</topic><topic>Leukemia, Myeloid, Acute - drug therapy</topic><topic>loci</topic><topic>lymphoma</topic><topic>Messenger RNA</topic><topic>Mice</topic><topic>Mice, Inbred NOD</topic><topic>Mice, SCID</topic><topic>myeloid leukemia</topic><topic>Polymerase Chain Reaction</topic><topic>Protein Structure, Tertiary - genetics</topic><topic>Proteins</topic><topic>RNA, Small Interfering - genetics</topic><topic>transcription (genetics)</topic><topic>transcription factors</topic><topic>Transcription Factors - antagonists & inhibitors</topic><topic>Transcription Factors - genetics</topic><topic>Transcription Factors - metabolism</topic><topic>transcriptome</topic><topic>Triazoles - pharmacology</topic><topic>Tumors</topic><topic>Viability</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Mertz, Jennifer A</creatorcontrib><creatorcontrib>Conery, Andrew R</creatorcontrib><creatorcontrib>Bryant, Barbara M</creatorcontrib><creatorcontrib>Sandy, Peter</creatorcontrib><creatorcontrib>Balasubramanian, Srividya</creatorcontrib><creatorcontrib>Mele, Deanna A</creatorcontrib><creatorcontrib>Bergeron, Louise</creatorcontrib><creatorcontrib>Sims, Robert J., III</creatorcontrib><collection>AGRIS</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Animal Behavior Abstracts</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Ecology Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Mertz, Jennifer A</au><au>Conery, Andrew R</au><au>Bryant, Barbara M</au><au>Sandy, Peter</au><au>Balasubramanian, Srividya</au><au>Mele, Deanna A</au><au>Bergeron, Louise</au><au>Sims, Robert J., III</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Targeting MYC dependence in cancer by inhibiting BET bromodomains</atitle><jtitle>Proceedings of the National Academy of Sciences - PNAS</jtitle><addtitle>Proc Natl Acad Sci U S A</addtitle><date>2011-10-04</date><risdate>2011</risdate><volume>108</volume><issue>40</issue><spage>16669</spage><epage>16674</epage><pages>16669-16674</pages><issn>0027-8424</issn><eissn>1091-6490</eissn><abstract>The MYC transcription factor is a master regulator of diverse cellular functions and has been long considered a compelling therapeutic target because of its role in a range of human malignancies. However, pharmacologic inhibition of MYC function has proven challenging because of both the diverse mechanisms driving its aberrant expression and the challenge of disrupting protein–DNA interactions. Here, we demonstrate the rapid and potent abrogation of MYC gene transcription by representative small molecule inhibitors of the BET family of chromatin adaptors. MYC transcriptional suppression was observed in the context of the natural, chromosomally translocated, and amplified gene locus. Inhibition of BET bromodomain–promoter interactions and subsequent reduction of MYC transcript and protein levels resulted in G1 arrest and extensive apoptosis in a variety of leukemia and lymphoma cell lines. Exogenous expression of MYC from an artificial promoter that is resistant to BET regulation significantly protected cells from cell cycle arrest and growth suppression by BET inhibitors. MYC suppression was accompanied by deregulation of the MYC transcriptome, including potent reactivation of the p21 tumor suppressor. Treatment with a BET inhibitor resulted in significant antitumor activity in xenograft models of Burkitt's lymphoma and acute myeloid leukemia. These findings demonstrate that pharmacologic inhibition of MYC is achievable through targeting BET bromodomains. Such inhibitors may have clinical utility given the widespread pathogenetic role of MYC in cancer.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>21949397</pmid><doi>10.1073/pnas.1108190108</doi><tpages>6</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals anticarcinogenic activity Apoptosis Apoptosis - genetics Apoptosis - physiology Azepines - pharmacology Betting Biological Sciences Blotting, Western Burkitt Lymphoma - drug therapy Cancer Cell cycle Cell Cycle - physiology Cell Line, Tumor Cell lines Cell Proliferation - drug effects Chromatin Chromatin Immunoprecipitation chromosome translocation DNA-Binding Proteins - antagonists & inhibitors DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Dose-Response Relationship, Drug Flow Cytometry Gene expression Gene Expression Profiling Gene Expression Regulation, Neoplastic - drug effects Gene Expression Regulation, Neoplastic - physiology Genes Genetic loci HeLa cells Humans Leukemia, Myeloid, Acute - drug therapy loci lymphoma Messenger RNA Mice Mice, Inbred NOD Mice, SCID myeloid leukemia Polymerase Chain Reaction Protein Structure, Tertiary - genetics Proteins RNA, Small Interfering - genetics transcription (genetics) transcription factors Transcription Factors - antagonists & inhibitors Transcription Factors - genetics Transcription Factors - metabolism transcriptome Triazoles - pharmacology Tumors Viability |
| title | Targeting MYC dependence in cancer by inhibiting BET bromodomains |
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