FRMD6 has tumor suppressor functions in prostate cancer
Available tools for prostate cancer (PC) prognosis are suboptimal but may be improved by better knowledge about genes driving tumor aggressiveness. Here, we identified FRMD6 (FERM domain-containing protein 6) as an aberrantly hypermethylated and significantly downregulated gene in PC. Low FRMD6 expr...
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| Veröffentlicht in: | Oncogene 2021-01, Vol.40 (4), p.763-776 |
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| creator | Haldrup, Jakob Strand, Siri H. Cieza-Borrella, Clara Jakobsson, Magnus E. Riedel, Maria Norgaard, Maibritt Hedensted, Stine Dagnaes-Hansen, Frederik Ulhoi, Benedicte Parm Eeles, Rosalind Borre, Michael Olsen, Jesper V. Thomsen, Martin Kote-Jarai, Zsofia Sorensen, Karina D. |
| description | Available tools for prostate cancer (PC) prognosis are suboptimal but may be improved by better knowledge about genes driving tumor aggressiveness. Here, we identified
FRMD6
(FERM domain-containing protein 6) as an aberrantly hypermethylated and significantly downregulated gene in PC. Low FRMD6 expression was associated with postoperative biochemical recurrence in two large PC patient cohorts. In overexpression and CRISPR/Cas9 knockout experiments in PC cell lines, FRMD6 inhibited viability, proliferation, cell cycle progression, colony formation, 3D spheroid growth, and tumor xenograft growth in mice. Transcriptomic, proteomic, and phospho-proteomic profiling revealed enrichment of Hippo/YAP and c-MYC signaling upon
FRMD6
knockout. Connectivity Map analysis and drug repurposing experiments identified pyroxamide as a new potential therapy for
FRMD6
deficient PC cells. Finally, we established orthotropic
Frmd6
and
Pten
, or
Pten
only (control) knockout in the ROSA26 mouse prostate. After 12 weeks,
Frmd6/Pten
double knockouts presented high-grade prostatic intraepithelial neoplasia (HG-PIN) and hyperproliferation, while
Pten
single-knockouts developed only regular PIN lesions and displayed lower proliferation. In conclusion,
FRMD6
was identified as a novel tumor suppressor gene and prognostic biomarker candidate in PC. |
| doi_str_mv | 10.1038/s41388-020-01548-w |
| format | Article |
| fullrecord | <record><control><sourceid>gale_webof</sourceid><recordid>TN_cdi_gale_infotracacademiconefile_A655713976</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A655713976</galeid><sourcerecordid>A655713976</sourcerecordid><originalsourceid>FETCH-LOGICAL-c511t-917c421d54469e9441aea0c42de3a5ea50fc82371162ece2b694446a5c0e7d3f3</originalsourceid><addsrcrecordid>eNqNkl-L1DAUxYso7rj6BXyQgi-CdL353zwuo6vCiCD6HNL0Zs3SaWvTMvjtvWvHWRQRCSGX8DuHe3NSFE8ZXDAQ9assmajrCjhUwJSsq8O9YsOk0ZVSVt4vNmAVVJYLflY8yvkGAIwF_rA4E4JLK7nZFObq04fXuvzqczkv-2Eq8zKOE-ZMZVz6MKehz2Xqy3Ea8uxnLIPvA06PiwfRdxmfHM_z4svVm8_bd9Xu49v328tdFRRjc2WZCZKzVkmpLVopmUcPdNWi8Aq9ghhqLgxjmmNA3mhipPYqAJpWRHFe7FbffMBxadw4pb2fvrvBJ9ctI-2GtsvoUAcrtPdORtU4Gg5cHVtwMfpWkxfXwMjuxWpH43xbMM9un3LArvM9Dkt2XGpllAYjCH3-B3ozLFNPwxJFPStjtLmjrn2HLvVxmCcfbk3dpVbKMGGNJuriLxStFvcpDD3GRPe_CfgqCPTsecJ4GpyBuw3freE7Ct_9DN8dSPTs2PHS7LE9SX6lTUC9AgdshphDQoryhNH3oG-ja7BUAdsmipvS3w5LP5P05f9LiRbH1Ijor3G6e7t_9P8DJzTXpA</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2482357767</pqid></control><display><type>article</type><title>FRMD6 has tumor suppressor functions in prostate cancer</title><source>MEDLINE</source><source>Alma/SFX Local Collection</source><creator>Haldrup, Jakob ; Strand, Siri H. ; Cieza-Borrella, Clara ; Jakobsson, Magnus E. ; Riedel, Maria ; Norgaard, Maibritt ; Hedensted, Stine ; Dagnaes-Hansen, Frederik ; Ulhoi, Benedicte Parm ; Eeles, Rosalind ; Borre, Michael ; Olsen, Jesper V. ; Thomsen, Martin ; Kote-Jarai, Zsofia ; Sorensen, Karina D.</creator><creatorcontrib>Haldrup, Jakob ; Strand, Siri H. ; Cieza-Borrella, Clara ; Jakobsson, Magnus E. ; Riedel, Maria ; Norgaard, Maibritt ; Hedensted, Stine ; Dagnaes-Hansen, Frederik ; Ulhoi, Benedicte Parm ; Eeles, Rosalind ; Borre, Michael ; Olsen, Jesper V. ; Thomsen, Martin ; Kote-Jarai, Zsofia ; Sorensen, Karina D.</creatorcontrib><description>Available tools for prostate cancer (PC) prognosis are suboptimal but may be improved by better knowledge about genes driving tumor aggressiveness. Here, we identified
FRMD6
(FERM domain-containing protein 6) as an aberrantly hypermethylated and significantly downregulated gene in PC. Low FRMD6 expression was associated with postoperative biochemical recurrence in two large PC patient cohorts. In overexpression and CRISPR/Cas9 knockout experiments in PC cell lines, FRMD6 inhibited viability, proliferation, cell cycle progression, colony formation, 3D spheroid growth, and tumor xenograft growth in mice. Transcriptomic, proteomic, and phospho-proteomic profiling revealed enrichment of Hippo/YAP and c-MYC signaling upon
FRMD6
knockout. Connectivity Map analysis and drug repurposing experiments identified pyroxamide as a new potential therapy for
FRMD6
deficient PC cells. Finally, we established orthotropic
Frmd6
and
Pten
, or
Pten
only (control) knockout in the ROSA26 mouse prostate. After 12 weeks,
Frmd6/Pten
double knockouts presented high-grade prostatic intraepithelial neoplasia (HG-PIN) and hyperproliferation, while
Pten
single-knockouts developed only regular PIN lesions and displayed lower proliferation. In conclusion,
FRMD6
was identified as a novel tumor suppressor gene and prognostic biomarker candidate in PC.</description><identifier>ISSN: 0950-9232</identifier><identifier>ISSN: 1476-5594</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/s41388-020-01548-w</identifier><identifier>PMID: 33249427</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject><![CDATA[13 ; 42 ; 42/41 ; 45 ; 631/61/514 ; 631/67/589/466 ; 64 ; 64/60 ; 82 ; 82/58 ; Aged ; Aminopyridines - pharmacology ; Animals ; Apoptosis ; Biochemistry & Molecular Biology ; c-Myc protein ; Cancer and Oncology ; Cancer och onkologi ; Care and treatment ; Cell Biology ; Cell cycle ; Cell Proliferation ; Clinical Medicine ; CRISPR ; Cytoskeletal Proteins - genetics ; Cytoskeletal Proteins - physiology ; Development and progression ; DNA Methylation ; Down-Regulation ; Gene expression ; Genetic aspects ; Genetics & Heredity ; Health aspects ; Hippo Signaling Pathway ; Human Genetics ; Humans ; Hydroxamic Acids - pharmacology ; Internal Medicine ; Intracellular Signaling Peptides and Proteins - genetics ; Intracellular Signaling Peptides and Proteins - physiology ; Klinisk medicin ; Life Sciences & Biomedicine ; Male ; Medical and Health Sciences ; Medicin och hälsovetenskap ; Medicine ; Medicine & Public Health ; Membrane Proteins - genetics ; Membrane Proteins - physiology ; Mice ; Middle Aged ; Myc protein ; Oncology ; Pheochromocytoma cells ; Prognosis ; Promoter Regions, Genetic ; Prostate cancer ; Prostatic intraepithelial neoplasia ; Prostatic Neoplasms - pathology ; Prostatic Neoplasms - prevention & control ; Protein Serine-Threonine Kinases - physiology ; Proteomics ; PTEN Phosphohydrolase - physiology ; PTEN protein ; Science & Technology ; Tumor suppressor genes ; Tumor Suppressor Proteins - physiology ; Xenografts ; Yes-associated protein]]></subject><ispartof>Oncogene, 2021-01, Vol.40 (4), p.763-776</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited 2020</rights><rights>COPYRIGHT 2021 Nature Publishing Group</rights><rights>The Author(s), under exclusive licence to Springer Nature Limited 2020.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>true</woscitedreferencessubscribed><woscitedreferencescount>26</woscitedreferencescount><woscitedreferencesoriginalsourcerecordid>wos000594680900001</woscitedreferencesoriginalsourcerecordid><citedby>FETCH-LOGICAL-c511t-917c421d54469e9441aea0c42de3a5ea50fc82371162ece2b694446a5c0e7d3f3</citedby><cites>FETCH-LOGICAL-c511t-917c421d54469e9441aea0c42de3a5ea50fc82371162ece2b694446a5c0e7d3f3</cites><orcidid>0000-0002-4747-4938 ; 0000-0002-4902-5490 ; 0000-0002-5055-7531 ; 0000-0002-6329-5155 ; 0000-0003-2739-1040 ; 0000-0002-1519-9185 ; 0000-0002-3698-6241 ; 0000-0001-6596-9945 ; 0000-0002-6545-0243</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,315,781,785,886,27928,27929</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33249427$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://lup.lub.lu.se/record/e6c936aa-4f5b-4270-8fd0-ffad67d32601$$DView record from Swedish Publication Index$$Hfree_for_read</backlink></links><search><creatorcontrib>Haldrup, Jakob</creatorcontrib><creatorcontrib>Strand, Siri H.</creatorcontrib><creatorcontrib>Cieza-Borrella, Clara</creatorcontrib><creatorcontrib>Jakobsson, Magnus E.</creatorcontrib><creatorcontrib>Riedel, Maria</creatorcontrib><creatorcontrib>Norgaard, Maibritt</creatorcontrib><creatorcontrib>Hedensted, Stine</creatorcontrib><creatorcontrib>Dagnaes-Hansen, Frederik</creatorcontrib><creatorcontrib>Ulhoi, Benedicte Parm</creatorcontrib><creatorcontrib>Eeles, Rosalind</creatorcontrib><creatorcontrib>Borre, Michael</creatorcontrib><creatorcontrib>Olsen, Jesper V.</creatorcontrib><creatorcontrib>Thomsen, Martin</creatorcontrib><creatorcontrib>Kote-Jarai, Zsofia</creatorcontrib><creatorcontrib>Sorensen, Karina D.</creatorcontrib><title>FRMD6 has tumor suppressor functions in prostate cancer</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>ONCOGENE</addtitle><addtitle>Oncogene</addtitle><description>Available tools for prostate cancer (PC) prognosis are suboptimal but may be improved by better knowledge about genes driving tumor aggressiveness. Here, we identified
FRMD6
(FERM domain-containing protein 6) as an aberrantly hypermethylated and significantly downregulated gene in PC. Low FRMD6 expression was associated with postoperative biochemical recurrence in two large PC patient cohorts. In overexpression and CRISPR/Cas9 knockout experiments in PC cell lines, FRMD6 inhibited viability, proliferation, cell cycle progression, colony formation, 3D spheroid growth, and tumor xenograft growth in mice. Transcriptomic, proteomic, and phospho-proteomic profiling revealed enrichment of Hippo/YAP and c-MYC signaling upon
FRMD6
knockout. Connectivity Map analysis and drug repurposing experiments identified pyroxamide as a new potential therapy for
FRMD6
deficient PC cells. Finally, we established orthotropic
Frmd6
and
Pten
, or
Pten
only (control) knockout in the ROSA26 mouse prostate. After 12 weeks,
Frmd6/Pten
double knockouts presented high-grade prostatic intraepithelial neoplasia (HG-PIN) and hyperproliferation, while
Pten
single-knockouts developed only regular PIN lesions and displayed lower proliferation. In conclusion,
FRMD6
was identified as a novel tumor suppressor gene and prognostic biomarker candidate in PC.</description><subject>13</subject><subject>42</subject><subject>42/41</subject><subject>45</subject><subject>631/61/514</subject><subject>631/67/589/466</subject><subject>64</subject><subject>64/60</subject><subject>82</subject><subject>82/58</subject><subject>Aged</subject><subject>Aminopyridines - pharmacology</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Biochemistry & Molecular Biology</subject><subject>c-Myc protein</subject><subject>Cancer and Oncology</subject><subject>Cancer och onkologi</subject><subject>Care and treatment</subject><subject>Cell Biology</subject><subject>Cell cycle</subject><subject>Cell Proliferation</subject><subject>Clinical Medicine</subject><subject>CRISPR</subject><subject>Cytoskeletal Proteins - genetics</subject><subject>Cytoskeletal Proteins - physiology</subject><subject>Development and progression</subject><subject>DNA Methylation</subject><subject>Down-Regulation</subject><subject>Gene expression</subject><subject>Genetic aspects</subject><subject>Genetics & Heredity</subject><subject>Health aspects</subject><subject>Hippo Signaling Pathway</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Hydroxamic Acids - pharmacology</subject><subject>Internal Medicine</subject><subject>Intracellular Signaling Peptides and Proteins - genetics</subject><subject>Intracellular Signaling Peptides and Proteins - physiology</subject><subject>Klinisk medicin</subject><subject>Life Sciences & Biomedicine</subject><subject>Male</subject><subject>Medical and Health Sciences</subject><subject>Medicin och hälsovetenskap</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Membrane Proteins - genetics</subject><subject>Membrane Proteins - physiology</subject><subject>Mice</subject><subject>Middle Aged</subject><subject>Myc protein</subject><subject>Oncology</subject><subject>Pheochromocytoma cells</subject><subject>Prognosis</subject><subject>Promoter Regions, Genetic</subject><subject>Prostate cancer</subject><subject>Prostatic intraepithelial neoplasia</subject><subject>Prostatic Neoplasms - pathology</subject><subject>Prostatic Neoplasms - prevention & control</subject><subject>Protein Serine-Threonine Kinases - physiology</subject><subject>Proteomics</subject><subject>PTEN Phosphohydrolase - physiology</subject><subject>PTEN protein</subject><subject>Science & Technology</subject><subject>Tumor suppressor genes</subject><subject>Tumor Suppressor Proteins - physiology</subject><subject>Xenografts</subject><subject>Yes-associated protein</subject><issn>0950-9232</issn><issn>1476-5594</issn><issn>1476-5594</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>HGBXW</sourceid><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNqNkl-L1DAUxYso7rj6BXyQgi-CdL353zwuo6vCiCD6HNL0Zs3SaWvTMvjtvWvHWRQRCSGX8DuHe3NSFE8ZXDAQ9assmajrCjhUwJSsq8O9YsOk0ZVSVt4vNmAVVJYLflY8yvkGAIwF_rA4E4JLK7nZFObq04fXuvzqczkv-2Eq8zKOE-ZMZVz6MKehz2Xqy3Ea8uxnLIPvA06PiwfRdxmfHM_z4svVm8_bd9Xu49v328tdFRRjc2WZCZKzVkmpLVopmUcPdNWi8Aq9ghhqLgxjmmNA3mhipPYqAJpWRHFe7FbffMBxadw4pb2fvrvBJ9ctI-2GtsvoUAcrtPdORtU4Gg5cHVtwMfpWkxfXwMjuxWpH43xbMM9un3LArvM9Dkt2XGpllAYjCH3-B3ozLFNPwxJFPStjtLmjrn2HLvVxmCcfbk3dpVbKMGGNJuriLxStFvcpDD3GRPe_CfgqCPTsecJ4GpyBuw3freE7Ct_9DN8dSPTs2PHS7LE9SX6lTUC9AgdshphDQoryhNH3oG-ja7BUAdsmipvS3w5LP5P05f9LiRbH1Ijor3G6e7t_9P8DJzTXpA</recordid><startdate>20210128</startdate><enddate>20210128</enddate><creator>Haldrup, Jakob</creator><creator>Strand, Siri H.</creator><creator>Cieza-Borrella, Clara</creator><creator>Jakobsson, Magnus E.</creator><creator>Riedel, Maria</creator><creator>Norgaard, Maibritt</creator><creator>Hedensted, Stine</creator><creator>Dagnaes-Hansen, Frederik</creator><creator>Ulhoi, Benedicte Parm</creator><creator>Eeles, Rosalind</creator><creator>Borre, Michael</creator><creator>Olsen, Jesper V.</creator><creator>Thomsen, Martin</creator><creator>Kote-Jarai, Zsofia</creator><creator>Sorensen, Karina D.</creator><general>Nature Publishing Group UK</general><general>Springer Nature</general><general>Nature Publishing Group</general><scope>BLEPL</scope><scope>DTL</scope><scope>HGBXW</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><scope>ADTPV</scope><scope>AOWAS</scope><scope>D95</scope><orcidid>https://orcid.org/0000-0002-4747-4938</orcidid><orcidid>https://orcid.org/0000-0002-4902-5490</orcidid><orcidid>https://orcid.org/0000-0002-5055-7531</orcidid><orcidid>https://orcid.org/0000-0002-6329-5155</orcidid><orcidid>https://orcid.org/0000-0003-2739-1040</orcidid><orcidid>https://orcid.org/0000-0002-1519-9185</orcidid><orcidid>https://orcid.org/0000-0002-3698-6241</orcidid><orcidid>https://orcid.org/0000-0001-6596-9945</orcidid><orcidid>https://orcid.org/0000-0002-6545-0243</orcidid></search><sort><creationdate>20210128</creationdate><title>FRMD6 has tumor suppressor functions in prostate cancer</title><author>Haldrup, Jakob ; Strand, Siri H. ; Cieza-Borrella, Clara ; Jakobsson, Magnus E. ; Riedel, Maria ; Norgaard, Maibritt ; Hedensted, Stine ; Dagnaes-Hansen, Frederik ; Ulhoi, Benedicte Parm ; Eeles, Rosalind ; Borre, Michael ; Olsen, Jesper V. ; Thomsen, Martin ; Kote-Jarai, Zsofia ; Sorensen, Karina D.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c511t-917c421d54469e9441aea0c42de3a5ea50fc82371162ece2b694446a5c0e7d3f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>13</topic><topic>42</topic><topic>42/41</topic><topic>45</topic><topic>631/61/514</topic><topic>631/67/589/466</topic><topic>64</topic><topic>64/60</topic><topic>82</topic><topic>82/58</topic><topic>Aged</topic><topic>Aminopyridines - pharmacology</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Biochemistry & Molecular Biology</topic><topic>c-Myc protein</topic><topic>Cancer and Oncology</topic><topic>Cancer och onkologi</topic><topic>Care and treatment</topic><topic>Cell Biology</topic><topic>Cell cycle</topic><topic>Cell Proliferation</topic><topic>Clinical Medicine</topic><topic>CRISPR</topic><topic>Cytoskeletal Proteins - genetics</topic><topic>Cytoskeletal Proteins - physiology</topic><topic>Development and progression</topic><topic>DNA Methylation</topic><topic>Down-Regulation</topic><topic>Gene expression</topic><topic>Genetic aspects</topic><topic>Genetics & Heredity</topic><topic>Health aspects</topic><topic>Hippo Signaling Pathway</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Hydroxamic Acids - pharmacology</topic><topic>Internal Medicine</topic><topic>Intracellular Signaling Peptides and Proteins - genetics</topic><topic>Intracellular Signaling Peptides and Proteins - physiology</topic><topic>Klinisk medicin</topic><topic>Life Sciences & Biomedicine</topic><topic>Male</topic><topic>Medical and Health Sciences</topic><topic>Medicin och hälsovetenskap</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Membrane Proteins - 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Academic</collection><collection>SwePub</collection><collection>SwePub Articles</collection><collection>SWEPUB Lunds universitet</collection><jtitle>Oncogene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Haldrup, Jakob</au><au>Strand, Siri H.</au><au>Cieza-Borrella, Clara</au><au>Jakobsson, Magnus E.</au><au>Riedel, Maria</au><au>Norgaard, Maibritt</au><au>Hedensted, Stine</au><au>Dagnaes-Hansen, Frederik</au><au>Ulhoi, Benedicte Parm</au><au>Eeles, Rosalind</au><au>Borre, Michael</au><au>Olsen, Jesper V.</au><au>Thomsen, Martin</au><au>Kote-Jarai, Zsofia</au><au>Sorensen, Karina D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>FRMD6 has tumor suppressor functions in prostate cancer</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><stitle>ONCOGENE</stitle><addtitle>Oncogene</addtitle><date>2021-01-28</date><risdate>2021</risdate><volume>40</volume><issue>4</issue><spage>763</spage><epage>776</epage><pages>763-776</pages><issn>0950-9232</issn><issn>1476-5594</issn><eissn>1476-5594</eissn><abstract>Available tools for prostate cancer (PC) prognosis are suboptimal but may be improved by better knowledge about genes driving tumor aggressiveness. Here, we identified
FRMD6
(FERM domain-containing protein 6) as an aberrantly hypermethylated and significantly downregulated gene in PC. Low FRMD6 expression was associated with postoperative biochemical recurrence in two large PC patient cohorts. In overexpression and CRISPR/Cas9 knockout experiments in PC cell lines, FRMD6 inhibited viability, proliferation, cell cycle progression, colony formation, 3D spheroid growth, and tumor xenograft growth in mice. Transcriptomic, proteomic, and phospho-proteomic profiling revealed enrichment of Hippo/YAP and c-MYC signaling upon
FRMD6
knockout. Connectivity Map analysis and drug repurposing experiments identified pyroxamide as a new potential therapy for
FRMD6
deficient PC cells. Finally, we established orthotropic
Frmd6
and
Pten
, or
Pten
only (control) knockout in the ROSA26 mouse prostate. After 12 weeks,
Frmd6/Pten
double knockouts presented high-grade prostatic intraepithelial neoplasia (HG-PIN) and hyperproliferation, while
Pten
single-knockouts developed only regular PIN lesions and displayed lower proliferation. In conclusion,
FRMD6
was identified as a novel tumor suppressor gene and prognostic biomarker candidate in PC.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>33249427</pmid><doi>10.1038/s41388-020-01548-w</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0002-4747-4938</orcidid><orcidid>https://orcid.org/0000-0002-4902-5490</orcidid><orcidid>https://orcid.org/0000-0002-5055-7531</orcidid><orcidid>https://orcid.org/0000-0002-6329-5155</orcidid><orcidid>https://orcid.org/0000-0003-2739-1040</orcidid><orcidid>https://orcid.org/0000-0002-1519-9185</orcidid><orcidid>https://orcid.org/0000-0002-3698-6241</orcidid><orcidid>https://orcid.org/0000-0001-6596-9945</orcidid><orcidid>https://orcid.org/0000-0002-6545-0243</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0950-9232 |
| ispartof | Oncogene, 2021-01, Vol.40 (4), p.763-776 |
| issn | 0950-9232 1476-5594 1476-5594 |
| language | eng |
| recordid | cdi_gale_infotracacademiconefile_A655713976 |
| source | MEDLINE; Alma/SFX Local Collection |
| subjects | 13 42 42/41 45 631/61/514 631/67/589/466 64 64/60 82 82/58 Aged Aminopyridines - pharmacology Animals Apoptosis Biochemistry & Molecular Biology c-Myc protein Cancer and Oncology Cancer och onkologi Care and treatment Cell Biology Cell cycle Cell Proliferation Clinical Medicine CRISPR Cytoskeletal Proteins - genetics Cytoskeletal Proteins - physiology Development and progression DNA Methylation Down-Regulation Gene expression Genetic aspects Genetics & Heredity Health aspects Hippo Signaling Pathway Human Genetics Humans Hydroxamic Acids - pharmacology Internal Medicine Intracellular Signaling Peptides and Proteins - genetics Intracellular Signaling Peptides and Proteins - physiology Klinisk medicin Life Sciences & Biomedicine Male Medical and Health Sciences Medicin och hälsovetenskap Medicine Medicine & Public Health Membrane Proteins - genetics Membrane Proteins - physiology Mice Middle Aged Myc protein Oncology Pheochromocytoma cells Prognosis Promoter Regions, Genetic Prostate cancer Prostatic intraepithelial neoplasia Prostatic Neoplasms - pathology Prostatic Neoplasms - prevention & control Protein Serine-Threonine Kinases - physiology Proteomics PTEN Phosphohydrolase - physiology PTEN protein Science & Technology Tumor suppressor genes Tumor Suppressor Proteins - physiology Xenografts Yes-associated protein |
| title | FRMD6 has tumor suppressor functions in prostate cancer |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-17T07%3A43%3A20IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-gale_webof&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=FRMD6%20has%20tumor%20suppressor%20functions%20in%20prostate%20cancer&rft.jtitle=Oncogene&rft.au=Haldrup,%20Jakob&rft.date=2021-01-28&rft.volume=40&rft.issue=4&rft.spage=763&rft.epage=776&rft.pages=763-776&rft.issn=0950-9232&rft.eissn=1476-5594&rft_id=info:doi/10.1038/s41388-020-01548-w&rft_dat=%3Cgale_webof%3EA655713976%3C/gale_webof%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2482357767&rft_id=info:pmid/33249427&rft_galeid=A655713976&rfr_iscdi=true |