YEATS4 is a novel oncogene amplified in non-small cell lung cancer that regulates the p53 pathway
Genetic analyses of lung cancer have helped found new treatments in this disease. We conducted an integrative analysis of gene expression and copy number in 261 non-small cell lung cancers (NSCLC) relative to matched normal tissues to define novel candidate oncogenes, identifying 12q13-15 and more s...
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| Veröffentlicht in: | Cancer research (Chicago, Ill.) Ill.), 2013-12, Vol.73 (24), p.7301-7312 |
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| container_title | Cancer research (Chicago, Ill.) |
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| creator | Pikor, Larissa A Lockwood, William W Thu, Kelsie L Vucic, Emily A Chari, Raj Gazdar, Adi F Lam, Stephen Lam, Wan L |
| description | Genetic analyses of lung cancer have helped found new treatments in this disease. We conducted an integrative analysis of gene expression and copy number in 261 non-small cell lung cancers (NSCLC) relative to matched normal tissues to define novel candidate oncogenes, identifying 12q13-15 and more specifically the YEATS4 gene as amplified and overexpressed in ~20% of the NSCLC cases examined. Overexpression of YEATS4 abrogated senescence in human bronchial epithelial cells. Conversely, RNAi-mediated attenuation of YEATS4 in human lung cancer cells reduced their proliferation and tumor growth, impairing colony formation and inducing cellular senescence. These effects were associated with increased levels of p21WAF1 and p53 and cleavage of PARP, implicating YEATS4 as a negative regulator of the p21-p53 pathway. We also found that YEATS4 expression affected cellular responses to cisplastin, with increased levels associated with resistance and decreased levels with sensitivity. Taken together, our findings reveal YEATS4 as a candidate oncogene amplified in NSCLC, and a novel mechanism contributing to NSCLC pathogenesis. |
| doi_str_mv | 10.1158/0008-5472.CAN-13-1897 |
| format | Article |
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We conducted an integrative analysis of gene expression and copy number in 261 non-small cell lung cancers (NSCLC) relative to matched normal tissues to define novel candidate oncogenes, identifying 12q13-15 and more specifically the YEATS4 gene as amplified and overexpressed in ~20% of the NSCLC cases examined. Overexpression of YEATS4 abrogated senescence in human bronchial epithelial cells. Conversely, RNAi-mediated attenuation of YEATS4 in human lung cancer cells reduced their proliferation and tumor growth, impairing colony formation and inducing cellular senescence. These effects were associated with increased levels of p21WAF1 and p53 and cleavage of PARP, implicating YEATS4 as a negative regulator of the p21-p53 pathway. We also found that YEATS4 expression affected cellular responses to cisplastin, with increased levels associated with resistance and decreased levels with sensitivity. Taken together, our findings reveal YEATS4 as a candidate oncogene amplified in NSCLC, and a novel mechanism contributing to NSCLC pathogenesis.</description><identifier>ISSN: 0008-5472</identifier><identifier>EISSN: 1538-7445</identifier><identifier>DOI: 10.1158/0008-5472.CAN-13-1897</identifier><identifier>PMID: 24170126</identifier><language>eng</language><publisher>United States</publisher><subject>Animals ; Carcinoma, Non-Small-Cell Lung - genetics ; Carcinoma, Non-Small-Cell Lung - metabolism ; Carcinoma, Non-Small-Cell Lung - pathology ; Cell Growth Processes - genetics ; Cyclin-Dependent Kinase Inhibitor p21 - genetics ; Cyclin-Dependent Kinase Inhibitor p21 - metabolism ; Gene Amplification ; Gene Expression Profiling ; Heterografts ; Humans ; Lung Neoplasms - genetics ; Lung Neoplasms - metabolism ; Lung Neoplasms - pathology ; Mice ; Mice, Inbred NOD ; Mice, SCID ; Nucleic Acid Hybridization ; Transcription Factors - genetics ; Transfection ; Tumor Suppressor Protein p53 - genetics ; Tumor Suppressor Protein p53 - metabolism</subject><ispartof>Cancer research (Chicago, Ill.), 2013-12, Vol.73 (24), p.7301-7312</ispartof><rights>2013 AACR.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c496t-88821f51f6c187c255dedfb4da60dccd368548b6e123ff3ac60dea08e91846cc3</citedby><cites>FETCH-LOGICAL-c496t-88821f51f6c187c255dedfb4da60dccd368548b6e123ff3ac60dea08e91846cc3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,781,785,886,3357,27929,27930</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24170126$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Pikor, Larissa A</creatorcontrib><creatorcontrib>Lockwood, William W</creatorcontrib><creatorcontrib>Thu, Kelsie L</creatorcontrib><creatorcontrib>Vucic, Emily A</creatorcontrib><creatorcontrib>Chari, Raj</creatorcontrib><creatorcontrib>Gazdar, Adi F</creatorcontrib><creatorcontrib>Lam, Stephen</creatorcontrib><creatorcontrib>Lam, Wan L</creatorcontrib><title>YEATS4 is a novel oncogene amplified in non-small cell lung cancer that regulates the p53 pathway</title><title>Cancer research (Chicago, Ill.)</title><addtitle>Cancer Res</addtitle><description>Genetic analyses of lung cancer have helped found new treatments in this disease. We conducted an integrative analysis of gene expression and copy number in 261 non-small cell lung cancers (NSCLC) relative to matched normal tissues to define novel candidate oncogenes, identifying 12q13-15 and more specifically the YEATS4 gene as amplified and overexpressed in ~20% of the NSCLC cases examined. Overexpression of YEATS4 abrogated senescence in human bronchial epithelial cells. Conversely, RNAi-mediated attenuation of YEATS4 in human lung cancer cells reduced their proliferation and tumor growth, impairing colony formation and inducing cellular senescence. These effects were associated with increased levels of p21WAF1 and p53 and cleavage of PARP, implicating YEATS4 as a negative regulator of the p21-p53 pathway. We also found that YEATS4 expression affected cellular responses to cisplastin, with increased levels associated with resistance and decreased levels with sensitivity. Taken together, our findings reveal YEATS4 as a candidate oncogene amplified in NSCLC, and a novel mechanism contributing to NSCLC pathogenesis.</description><subject>Animals</subject><subject>Carcinoma, Non-Small-Cell Lung - genetics</subject><subject>Carcinoma, Non-Small-Cell Lung - metabolism</subject><subject>Carcinoma, Non-Small-Cell Lung - pathology</subject><subject>Cell Growth Processes - genetics</subject><subject>Cyclin-Dependent Kinase Inhibitor p21 - genetics</subject><subject>Cyclin-Dependent Kinase Inhibitor p21 - metabolism</subject><subject>Gene Amplification</subject><subject>Gene Expression Profiling</subject><subject>Heterografts</subject><subject>Humans</subject><subject>Lung Neoplasms - genetics</subject><subject>Lung Neoplasms - metabolism</subject><subject>Lung Neoplasms - pathology</subject><subject>Mice</subject><subject>Mice, Inbred NOD</subject><subject>Mice, SCID</subject><subject>Nucleic Acid Hybridization</subject><subject>Transcription Factors - genetics</subject><subject>Transfection</subject><subject>Tumor Suppressor Protein p53 - genetics</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><issn>0008-5472</issn><issn>1538-7445</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUUtP3DAQtlAr2NL-hFY-9hLqiR9xLkirFY9KiB4KB07WrDPZTZU4IU5A_Ps6gq7KZUYz8803j4-xryDOALT9IYSwmVZFfrZZ32YgM7BlccRWoKXNCqX0B7Y6YE7Ypxj_pFCD0MfsJFdQCMjNiuHDxfrut-JN5MhD_0Qt74PvdxSIYze0Td1QxZuQaiGLHbYt95RMO4cd9xg8jXza48RH2s0tThRTSHzQkg847Z_x5TP7WGMb6cubP2X3lxd3m-vs5tfVz836JvOqNFNmrc2h1lAbD7bwudYVVfVWVWhE5X0ljdXKbg1BLutaok9pQmGpBKuM9_KUnb_yDvO2o8pTmEZs3TA2HY4vrsfGva-EZu92_ZOTpS5tIRLB9zeCsX-cKU6ua-JyLAbq5-hAazC5lAYSVL9C_djHOFJ9GAPCLfK45fVueb1L8jiQbpEn9X37f8dD1z895F9XiYyl</recordid><startdate>20131215</startdate><enddate>20131215</enddate><creator>Pikor, Larissa A</creator><creator>Lockwood, William W</creator><creator>Thu, Kelsie L</creator><creator>Vucic, Emily A</creator><creator>Chari, Raj</creator><creator>Gazdar, Adi F</creator><creator>Lam, Stephen</creator><creator>Lam, Wan L</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>7TO</scope><scope>H94</scope><scope>5PM</scope></search><sort><creationdate>20131215</creationdate><title>YEATS4 is a novel oncogene amplified in non-small cell lung cancer that regulates the p53 pathway</title><author>Pikor, Larissa A ; Lockwood, William W ; Thu, Kelsie L ; Vucic, Emily A ; Chari, Raj ; Gazdar, Adi F ; Lam, Stephen ; Lam, Wan L</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c496t-88821f51f6c187c255dedfb4da60dccd368548b6e123ff3ac60dea08e91846cc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Animals</topic><topic>Carcinoma, Non-Small-Cell Lung - genetics</topic><topic>Carcinoma, Non-Small-Cell Lung - metabolism</topic><topic>Carcinoma, Non-Small-Cell Lung - pathology</topic><topic>Cell Growth Processes - genetics</topic><topic>Cyclin-Dependent Kinase Inhibitor p21 - genetics</topic><topic>Cyclin-Dependent Kinase Inhibitor p21 - metabolism</topic><topic>Gene Amplification</topic><topic>Gene Expression Profiling</topic><topic>Heterografts</topic><topic>Humans</topic><topic>Lung Neoplasms - genetics</topic><topic>Lung Neoplasms - metabolism</topic><topic>Lung Neoplasms - pathology</topic><topic>Mice</topic><topic>Mice, Inbred NOD</topic><topic>Mice, SCID</topic><topic>Nucleic Acid Hybridization</topic><topic>Transcription Factors - genetics</topic><topic>Transfection</topic><topic>Tumor Suppressor Protein p53 - genetics</topic><topic>Tumor Suppressor Protein p53 - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Pikor, Larissa A</creatorcontrib><creatorcontrib>Lockwood, William W</creatorcontrib><creatorcontrib>Thu, Kelsie L</creatorcontrib><creatorcontrib>Vucic, Emily A</creatorcontrib><creatorcontrib>Chari, Raj</creatorcontrib><creatorcontrib>Gazdar, Adi F</creatorcontrib><creatorcontrib>Lam, Stephen</creatorcontrib><creatorcontrib>Lam, Wan L</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>AIDS and Cancer Research 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>Pikor, Larissa A</au><au>Lockwood, William W</au><au>Thu, Kelsie L</au><au>Vucic, Emily A</au><au>Chari, Raj</au><au>Gazdar, Adi F</au><au>Lam, Stephen</au><au>Lam, Wan L</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>YEATS4 is a novel oncogene amplified in non-small cell lung cancer that regulates the p53 pathway</atitle><jtitle>Cancer research (Chicago, Ill.)</jtitle><addtitle>Cancer Res</addtitle><date>2013-12-15</date><risdate>2013</risdate><volume>73</volume><issue>24</issue><spage>7301</spage><epage>7312</epage><pages>7301-7312</pages><issn>0008-5472</issn><eissn>1538-7445</eissn><abstract>Genetic analyses of lung cancer have helped found new treatments in this disease. We conducted an integrative analysis of gene expression and copy number in 261 non-small cell lung cancers (NSCLC) relative to matched normal tissues to define novel candidate oncogenes, identifying 12q13-15 and more specifically the YEATS4 gene as amplified and overexpressed in ~20% of the NSCLC cases examined. Overexpression of YEATS4 abrogated senescence in human bronchial epithelial cells. Conversely, RNAi-mediated attenuation of YEATS4 in human lung cancer cells reduced their proliferation and tumor growth, impairing colony formation and inducing cellular senescence. These effects were associated with increased levels of p21WAF1 and p53 and cleavage of PARP, implicating YEATS4 as a negative regulator of the p21-p53 pathway. We also found that YEATS4 expression affected cellular responses to cisplastin, with increased levels associated with resistance and decreased levels with sensitivity. 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| source | MEDLINE; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; American Association for Cancer Research |
| subjects | Animals Carcinoma, Non-Small-Cell Lung - genetics Carcinoma, Non-Small-Cell Lung - metabolism Carcinoma, Non-Small-Cell Lung - pathology Cell Growth Processes - genetics Cyclin-Dependent Kinase Inhibitor p21 - genetics Cyclin-Dependent Kinase Inhibitor p21 - metabolism Gene Amplification Gene Expression Profiling Heterografts Humans Lung Neoplasms - genetics Lung Neoplasms - metabolism Lung Neoplasms - pathology Mice Mice, Inbred NOD Mice, SCID Nucleic Acid Hybridization Transcription Factors - genetics Transfection Tumor Suppressor Protein p53 - genetics Tumor Suppressor Protein p53 - metabolism |
| title | YEATS4 is a novel oncogene amplified in non-small cell lung cancer that regulates the p53 pathway |
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