Altered SMRT levels disrupt vitamin D3 receptor signalling in prostate cancer cells
We hypothesized that key antiproliferative target genes for the vitamin D receptor (VDR) were repressed by an epigenetic mechanism in prostate cancer cells resulting in apparent hormonal insensitivity. To explore this possibility, we examined nuclear receptor corepressor expression in a panel of non...
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| Veröffentlicht in: | Oncogene 2004-09, Vol.23 (40), p.6712-6725 |
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| creator | Khanim, Farhat L Gommersall, Lyndon M Wood, Victoria HJ Smith, Kirsty L Montalvo, Leire O'Neill, Laura P Xu, Yue Peehl, Donna M Stewart, Paul M Turner, Bryan M Campbell, Moray J |
| description | We hypothesized that key antiproliferative target genes for the vitamin D receptor (VDR) were repressed by an epigenetic mechanism in prostate cancer cells resulting in apparent hormonal insensitivity. To explore this possibility, we examined nuclear receptor corepressor expression in a panel of nonmalignant and malignant cell lines and primary cultures, and found frequently elevated SMRT corepressor mRNA expression often associated with reduced sensitivity to 1
α
,25-dihydroxyvitamin D
3
(1
α
,25(OH)
2
D
3
). For example, PC-3 and DU-145 prostate cancer cell lines had 1.8-fold and twofold increases in SMRT mRNA relative to normal PrEC cells (
P |
| doi_str_mv | 10.1038/sj.onc.1207772 |
| format | Article |
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α
,25-dihydroxyvitamin D
3
(1
α
,25(OH)
2
D
3
). For example, PC-3 and DU-145 prostate cancer cell lines had 1.8-fold and twofold increases in SMRT mRNA relative to normal PrEC cells (
P
<0.05). Similarly, 10/15 primary tumour cultures (including three matched to normal cells from the same donors) had elevated SMRT mRNA levels; generally NCoR1 and Alien were not as commonly elevated. Corepressor proteins often have associated histone deacetylases (HDAC) and reflectively the antiproliferative action of 1
α
,25(OH)
2
D
3
can be ‘restored’ by cotreatment with low doses of HDAC inhibitors such as trichostatin A (TSA, 15 n
M
) to induce apoptosis in prostate cancer cell lines. To decipher the transcriptional events that lead to these cellular responses, we undertook gene expression studies in PC-3 cells after cotreatment of 1
α
,25(OH)
2
D
3
plus TSA after 6 h. Examination of known VDR target genes and cDNA microarray analyses revealed cotreatment of 1
α
,25(OH)
2
D
3
plus TSA cooperatively upregulated eight (out of 1176) genes, including MAPK-APK2 and GADD45
α
. MRNA and protein time courses and inhibitor studies confirmed these patterns of regulation. Subsequently, we knocked down SMRT levels in PC-3 cells using a small interfering RNA (siRNA) approach and found that GADD45
α
induction by 1
α
,25(OH)
2
D
3
alone became very significantly enhanced. The same distortion of gene responsiveness, with repressed induction of GADD45
α
was found in primary tumour cultures compared and to matched peripheral zone (normal) cultures from the same donor. These data demonstrate that elevated SMRT levels are common in prostate cancer cells, resulting in suppression of target genes associated with antiproliferative action and apparent 1
α
,25(OH)
2
D
3
-insensitivity. This can be targeted therapeutically by combination treatments with HDAC inhibitors.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/sj.onc.1207772</identifier><identifier>PMID: 15300237</identifier><identifier>CODEN: ONCNES</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>Apoptosis ; Base Sequence ; Biological and medical sciences ; Biomedical research ; Calcitriol - metabolism ; Cell Biology ; Cell Division ; Cell Line ; Cell Line, Tumor ; Cell physiology ; Cell receptors ; Cell structures and functions ; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes ; Cells, Cultured ; DNA microarrays ; DNA Primers ; DNA-Binding Proteins - genetics ; DNA-Binding Proteins - metabolism ; Dopamine D3 receptors ; Epigenetics ; Epithelial Cells - cytology ; Epithelial Cells - drug effects ; Fundamental and applied biological sciences. Psychology ; Gene expression ; Genes ; Histone deacetylase ; Histones ; Human Genetics ; Humans ; Internal Medicine ; Ligands ; Male ; MAP kinase ; Medical sciences ; Medicine ; Medicine & Public Health ; Miscellaneous ; Molecular and cellular biology ; Nephrology. Urinary tract diseases ; Nuclear Receptor Co-Repressor 2 ; Oligonucleotide Array Sequence Analysis ; Oncology ; original-paper ; Prostate - cytology ; Prostate cancer ; Prostatic Neoplasms ; Receptors, Calcitriol - physiology ; Repressor Proteins - genetics ; Repressor Proteins - metabolism ; Reverse Transcriptase Polymerase Chain Reaction ; RNA, Neoplasm - genetics ; RNA, Neoplasm - isolation & purification ; RNA, Small Interfering - genetics ; siRNA ; SMRT protein ; Transcription ; Transcription factors ; Trichostatin A ; Tumor cell lines ; Tumors ; Tumors of the urinary system ; Urinary tract. Prostate gland ; Vitamin D ; Vitamin D receptors ; Vitamin D3</subject><ispartof>Oncogene, 2004-09, Vol.23 (40), p.6712-6725</ispartof><rights>Springer Nature Limited 2004</rights><rights>2004 INIST-CNRS</rights><rights>COPYRIGHT 2004 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Sep 2, 2004</rights><rights>Nature Publishing Group 2004.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4382-1dd88e8a70133ade04b0f85e6dfc75e60cd982ba79c5403bc8d77dc238d401ec3</citedby><cites>FETCH-LOGICAL-c4382-1dd88e8a70133ade04b0f85e6dfc75e60cd982ba79c5403bc8d77dc238d401ec3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/sj.onc.1207772$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/sj.onc.1207772$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=16100994$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15300237$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Khanim, Farhat L</creatorcontrib><creatorcontrib>Gommersall, Lyndon M</creatorcontrib><creatorcontrib>Wood, Victoria HJ</creatorcontrib><creatorcontrib>Smith, Kirsty L</creatorcontrib><creatorcontrib>Montalvo, Leire</creatorcontrib><creatorcontrib>O'Neill, Laura P</creatorcontrib><creatorcontrib>Xu, Yue</creatorcontrib><creatorcontrib>Peehl, Donna M</creatorcontrib><creatorcontrib>Stewart, Paul M</creatorcontrib><creatorcontrib>Turner, Bryan M</creatorcontrib><creatorcontrib>Campbell, Moray J</creatorcontrib><title>Altered SMRT levels disrupt vitamin D3 receptor signalling in prostate cancer cells</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>We hypothesized that key antiproliferative target genes for the vitamin D receptor (VDR) were repressed by an epigenetic mechanism in prostate cancer cells resulting in apparent hormonal insensitivity. To explore this possibility, we examined nuclear receptor corepressor expression in a panel of nonmalignant and malignant cell lines and primary cultures, and found frequently elevated SMRT corepressor mRNA expression often associated with reduced sensitivity to 1
α
,25-dihydroxyvitamin D
3
(1
α
,25(OH)
2
D
3
). For example, PC-3 and DU-145 prostate cancer cell lines had 1.8-fold and twofold increases in SMRT mRNA relative to normal PrEC cells (
P
<0.05). Similarly, 10/15 primary tumour cultures (including three matched to normal cells from the same donors) had elevated SMRT mRNA levels; generally NCoR1 and Alien were not as commonly elevated. Corepressor proteins often have associated histone deacetylases (HDAC) and reflectively the antiproliferative action of 1
α
,25(OH)
2
D
3
can be ‘restored’ by cotreatment with low doses of HDAC inhibitors such as trichostatin A (TSA, 15 n
M
) to induce apoptosis in prostate cancer cell lines. To decipher the transcriptional events that lead to these cellular responses, we undertook gene expression studies in PC-3 cells after cotreatment of 1
α
,25(OH)
2
D
3
plus TSA after 6 h. Examination of known VDR target genes and cDNA microarray analyses revealed cotreatment of 1
α
,25(OH)
2
D
3
plus TSA cooperatively upregulated eight (out of 1176) genes, including MAPK-APK2 and GADD45
α
. MRNA and protein time courses and inhibitor studies confirmed these patterns of regulation. Subsequently, we knocked down SMRT levels in PC-3 cells using a small interfering RNA (siRNA) approach and found that GADD45
α
induction by 1
α
,25(OH)
2
D
3
alone became very significantly enhanced. The same distortion of gene responsiveness, with repressed induction of GADD45
α
was found in primary tumour cultures compared and to matched peripheral zone (normal) cultures from the same donor. These data demonstrate that elevated SMRT levels are common in prostate cancer cells, resulting in suppression of target genes associated with antiproliferative action and apparent 1
α
,25(OH)
2
D
3
-insensitivity. This can be targeted therapeutically by combination treatments with HDAC inhibitors.</description><subject>Apoptosis</subject><subject>Base Sequence</subject><subject>Biological and medical sciences</subject><subject>Biomedical research</subject><subject>Calcitriol - metabolism</subject><subject>Cell Biology</subject><subject>Cell Division</subject><subject>Cell Line</subject><subject>Cell Line, Tumor</subject><subject>Cell physiology</subject><subject>Cell receptors</subject><subject>Cell structures and functions</subject><subject>Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes</subject><subject>Cells, Cultured</subject><subject>DNA microarrays</subject><subject>DNA Primers</subject><subject>DNA-Binding Proteins - genetics</subject><subject>DNA-Binding Proteins - metabolism</subject><subject>Dopamine D3 receptors</subject><subject>Epigenetics</subject><subject>Epithelial Cells - cytology</subject><subject>Epithelial Cells - drug effects</subject><subject>Fundamental and applied biological sciences. Psychology</subject><subject>Gene expression</subject><subject>Genes</subject><subject>Histone deacetylase</subject><subject>Histones</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Internal Medicine</subject><subject>Ligands</subject><subject>Male</subject><subject>MAP kinase</subject><subject>Medical sciences</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Miscellaneous</subject><subject>Molecular and cellular biology</subject><subject>Nephrology. Urinary tract diseases</subject><subject>Nuclear Receptor Co-Repressor 2</subject><subject>Oligonucleotide Array Sequence Analysis</subject><subject>Oncology</subject><subject>original-paper</subject><subject>Prostate - cytology</subject><subject>Prostate cancer</subject><subject>Prostatic Neoplasms</subject><subject>Receptors, Calcitriol - physiology</subject><subject>Repressor Proteins - genetics</subject><subject>Repressor Proteins - metabolism</subject><subject>Reverse Transcriptase Polymerase Chain Reaction</subject><subject>RNA, Neoplasm - genetics</subject><subject>RNA, Neoplasm - isolation & purification</subject><subject>RNA, Small Interfering - genetics</subject><subject>siRNA</subject><subject>SMRT protein</subject><subject>Transcription</subject><subject>Transcription factors</subject><subject>Trichostatin A</subject><subject>Tumor cell lines</subject><subject>Tumors</subject><subject>Tumors of the urinary system</subject><subject>Urinary tract. Prostate gland</subject><subject>Vitamin D</subject><subject>Vitamin D receptors</subject><subject>Vitamin D3</subject><issn>0950-9232</issn><issn>1476-5594</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp1kctrGzEQxkVpaVy31x6LaGhv64weu5KOJn1CSqFJz0KWZo3MPlxpN9D_vjJZMJQEHQY0v5lvZj5C3jLYMBD6Kh824-A3jINSij8jKyZVU9W1kc_JCkwNleGCX5BXOR8AQBngL8kFqwUAF2pFbrfdhAkDvf3x6452eI9dpiHmNB8neh8n18eBfhI0ocfjNCaa435wXReHPS2ZYxrz5Cak3g0eE_XYdfk1edG6LuObJa7J7y-f766_VTc_v36_3t5UXgrNKxaC1qidAiaECwhyB62usQmtVyWAD0bznVPG1xLEzuugVPBc6CCBoRdr8vGhb5niz4x5sn3MpwncgOOcbdNoyUzZf00u_wMP45zKGtnyRjIhGa9Nod4_SXElRKNAn1vtXYc2Du04JedPunbLtAFjjJCF2jxClRewj34csI3l_7ECXw6aE7b2mGLv0l_LwJ6Mtvlgi9F2MboUvFuGnXc9hjO-OFuADwvgsnddm4pBMZ-5hkHRPilfPXC5pIY9pvPWT0j_A4lzvj4</recordid><startdate>20040902</startdate><enddate>20040902</enddate><creator>Khanim, Farhat L</creator><creator>Gommersall, Lyndon M</creator><creator>Wood, Victoria HJ</creator><creator>Smith, Kirsty L</creator><creator>Montalvo, Leire</creator><creator>O'Neill, Laura P</creator><creator>Xu, Yue</creator><creator>Peehl, Donna M</creator><creator>Stewart, Paul M</creator><creator>Turner, Bryan M</creator><creator>Campbell, Moray J</creator><general>Nature Publishing Group UK</general><general>Nature Publishing</general><general>Nature Publishing Group</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>3V.</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88A</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8FD</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AZQEC</scope><scope>BBNVY</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FR3</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>LK8</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>M7P</scope><scope>MBDVC</scope><scope>P64</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>PRINS</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20040902</creationdate><title>Altered SMRT levels disrupt vitamin D3 receptor signalling in prostate cancer cells</title><author>Khanim, Farhat L ; Gommersall, Lyndon M ; Wood, Victoria HJ ; Smith, Kirsty L ; Montalvo, Leire ; O'Neill, Laura P ; Xu, Yue ; Peehl, Donna M ; Stewart, Paul M ; Turner, Bryan M ; Campbell, Moray J</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4382-1dd88e8a70133ade04b0f85e6dfc75e60cd982ba79c5403bc8d77dc238d401ec3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2004</creationdate><topic>Apoptosis</topic><topic>Base Sequence</topic><topic>Biological and medical sciences</topic><topic>Biomedical research</topic><topic>Calcitriol - metabolism</topic><topic>Cell Biology</topic><topic>Cell Division</topic><topic>Cell Line</topic><topic>Cell Line, Tumor</topic><topic>Cell physiology</topic><topic>Cell receptors</topic><topic>Cell structures and functions</topic><topic>Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes</topic><topic>Cells, Cultured</topic><topic>DNA microarrays</topic><topic>DNA Primers</topic><topic>DNA-Binding Proteins - genetics</topic><topic>DNA-Binding Proteins - metabolism</topic><topic>Dopamine D3 receptors</topic><topic>Epigenetics</topic><topic>Epithelial Cells - cytology</topic><topic>Epithelial Cells - drug effects</topic><topic>Fundamental and applied biological sciences. Psychology</topic><topic>Gene expression</topic><topic>Genes</topic><topic>Histone deacetylase</topic><topic>Histones</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Internal Medicine</topic><topic>Ligands</topic><topic>Male</topic><topic>MAP kinase</topic><topic>Medical sciences</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Miscellaneous</topic><topic>Molecular and cellular biology</topic><topic>Nephrology. Urinary tract diseases</topic><topic>Nuclear Receptor Co-Repressor 2</topic><topic>Oligonucleotide Array Sequence Analysis</topic><topic>Oncology</topic><topic>original-paper</topic><topic>Prostate - cytology</topic><topic>Prostate cancer</topic><topic>Prostatic Neoplasms</topic><topic>Receptors, Calcitriol - physiology</topic><topic>Repressor Proteins - genetics</topic><topic>Repressor Proteins - metabolism</topic><topic>Reverse Transcriptase Polymerase Chain Reaction</topic><topic>RNA, Neoplasm - genetics</topic><topic>RNA, Neoplasm - isolation & purification</topic><topic>RNA, Small Interfering - genetics</topic><topic>siRNA</topic><topic>SMRT protein</topic><topic>Transcription</topic><topic>Transcription factors</topic><topic>Trichostatin A</topic><topic>Tumor cell lines</topic><topic>Tumors</topic><topic>Tumors of the urinary system</topic><topic>Urinary tract. Prostate gland</topic><topic>Vitamin D</topic><topic>Vitamin D receptors</topic><topic>Vitamin D3</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Khanim, Farhat L</creatorcontrib><creatorcontrib>Gommersall, Lyndon M</creatorcontrib><creatorcontrib>Wood, Victoria HJ</creatorcontrib><creatorcontrib>Smith, Kirsty L</creatorcontrib><creatorcontrib>Montalvo, Leire</creatorcontrib><creatorcontrib>O'Neill, Laura P</creatorcontrib><creatorcontrib>Xu, Yue</creatorcontrib><creatorcontrib>Peehl, Donna M</creatorcontrib><creatorcontrib>Stewart, Paul M</creatorcontrib><creatorcontrib>Turner, Bryan M</creatorcontrib><creatorcontrib>Campbell, Moray J</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>ProQuest Central (Corporate)</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Health & Medical Collection</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Biology Database (Alumni Edition)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Technology Research Database</collection><collection>ProQuest SciTech Collection</collection><collection>ProQuest Natural Science Collection</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>Research Library (Alumni Edition)</collection><collection>ProQuest Central (Alumni Edition)</collection><collection>ProQuest Central UK/Ireland</collection><collection>ProQuest Central Essentials</collection><collection>Biological Science Collection</collection><collection>ProQuest Central</collection><collection>Natural Science Collection</collection><collection>ProQuest One Community College</collection><collection>ProQuest Central Korea</collection><collection>Engineering Research Database</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>ProQuest Central Student</collection><collection>Research Library Prep</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>SciTech Premium Collection</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>ProQuest Biological Science Collection</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>Medical Database</collection><collection>Research Library</collection><collection>Biological Science Database</collection><collection>Research Library (Corporate)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>ProQuest Central Basic</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Oncogene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Khanim, Farhat L</au><au>Gommersall, Lyndon M</au><au>Wood, Victoria HJ</au><au>Smith, Kirsty L</au><au>Montalvo, Leire</au><au>O'Neill, Laura P</au><au>Xu, Yue</au><au>Peehl, Donna M</au><au>Stewart, Paul M</au><au>Turner, Bryan M</au><au>Campbell, Moray J</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Altered SMRT levels disrupt vitamin D3 receptor signalling in prostate cancer cells</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><addtitle>Oncogene</addtitle><date>2004-09-02</date><risdate>2004</risdate><volume>23</volume><issue>40</issue><spage>6712</spage><epage>6725</epage><pages>6712-6725</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><coden>ONCNES</coden><abstract>We hypothesized that key antiproliferative target genes for the vitamin D receptor (VDR) were repressed by an epigenetic mechanism in prostate cancer cells resulting in apparent hormonal insensitivity. To explore this possibility, we examined nuclear receptor corepressor expression in a panel of nonmalignant and malignant cell lines and primary cultures, and found frequently elevated SMRT corepressor mRNA expression often associated with reduced sensitivity to 1
α
,25-dihydroxyvitamin D
3
(1
α
,25(OH)
2
D
3
). For example, PC-3 and DU-145 prostate cancer cell lines had 1.8-fold and twofold increases in SMRT mRNA relative to normal PrEC cells (
P
<0.05). Similarly, 10/15 primary tumour cultures (including three matched to normal cells from the same donors) had elevated SMRT mRNA levels; generally NCoR1 and Alien were not as commonly elevated. Corepressor proteins often have associated histone deacetylases (HDAC) and reflectively the antiproliferative action of 1
α
,25(OH)
2
D
3
can be ‘restored’ by cotreatment with low doses of HDAC inhibitors such as trichostatin A (TSA, 15 n
M
) to induce apoptosis in prostate cancer cell lines. To decipher the transcriptional events that lead to these cellular responses, we undertook gene expression studies in PC-3 cells after cotreatment of 1
α
,25(OH)
2
D
3
plus TSA after 6 h. Examination of known VDR target genes and cDNA microarray analyses revealed cotreatment of 1
α
,25(OH)
2
D
3
plus TSA cooperatively upregulated eight (out of 1176) genes, including MAPK-APK2 and GADD45
α
. MRNA and protein time courses and inhibitor studies confirmed these patterns of regulation. Subsequently, we knocked down SMRT levels in PC-3 cells using a small interfering RNA (siRNA) approach and found that GADD45
α
induction by 1
α
,25(OH)
2
D
3
alone became very significantly enhanced. The same distortion of gene responsiveness, with repressed induction of GADD45
α
was found in primary tumour cultures compared and to matched peripheral zone (normal) cultures from the same donor. These data demonstrate that elevated SMRT levels are common in prostate cancer cells, resulting in suppression of target genes associated with antiproliferative action and apparent 1
α
,25(OH)
2
D
3
-insensitivity. This can be targeted therapeutically by combination treatments with HDAC inhibitors.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>15300237</pmid><doi>10.1038/sj.onc.1207772</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0950-9232 |
| ispartof | Oncogene, 2004-09, Vol.23 (40), p.6712-6725 |
| issn | 0950-9232 1476-5594 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_66841992 |
| source | MEDLINE; Springer Nature - Complete Springer Journals; Nature; EZB-FREE-00999 freely available EZB journals |
| subjects | Apoptosis Base Sequence Biological and medical sciences Biomedical research Calcitriol - metabolism Cell Biology Cell Division Cell Line Cell Line, Tumor Cell physiology Cell receptors Cell structures and functions Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes Cells, Cultured DNA microarrays DNA Primers DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism Dopamine D3 receptors Epigenetics Epithelial Cells - cytology Epithelial Cells - drug effects Fundamental and applied biological sciences. Psychology Gene expression Genes Histone deacetylase Histones Human Genetics Humans Internal Medicine Ligands Male MAP kinase Medical sciences Medicine Medicine & Public Health Miscellaneous Molecular and cellular biology Nephrology. Urinary tract diseases Nuclear Receptor Co-Repressor 2 Oligonucleotide Array Sequence Analysis Oncology original-paper Prostate - cytology Prostate cancer Prostatic Neoplasms Receptors, Calcitriol - physiology Repressor Proteins - genetics Repressor Proteins - metabolism Reverse Transcriptase Polymerase Chain Reaction RNA, Neoplasm - genetics RNA, Neoplasm - isolation & purification RNA, Small Interfering - genetics siRNA SMRT protein Transcription Transcription factors Trichostatin A Tumor cell lines Tumors Tumors of the urinary system Urinary tract. Prostate gland Vitamin D Vitamin D receptors Vitamin D3 |
| title | Altered SMRT levels disrupt vitamin D3 receptor signalling in prostate cancer cells |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-01T17%3A00%3A56IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_proqu&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Altered%20SMRT%20levels%20disrupt%20vitamin%20D3%20receptor%20signalling%20in%20prostate%20cancer%20cells&rft.jtitle=Oncogene&rft.au=Khanim,%20Farhat%20L&rft.date=2004-09-02&rft.volume=23&rft.issue=40&rft.spage=6712&rft.epage=6725&rft.pages=6712-6725&rft.issn=0950-9232&rft.eissn=1476-5594&rft.coden=ONCNES&rft_id=info:doi/10.1038/sj.onc.1207772&rft_dat=%3Cgale_proqu%3EA189099934%3C/gale_proqu%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=227336708&rft_id=info:pmid/15300237&rft_galeid=A189099934&rfr_iscdi=true |