Sox2 antagonizes the Hippo pathway to maintain stemness in cancer cells
The repressive Hippo pathway has a profound tumour suppressive role in cancer by restraining the growth-promoting function of the transcriptional coactivator, YAP. We previously showed that the stem cell transcription factor Sox2 maintains cancer stem cells (CSCs) in osteosarcomas. We now report tha...
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| Veröffentlicht in: | Nature communications 2015-04, Vol.6 (1), p.6411-6411, Article 6411 |
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| description | The repressive Hippo pathway has a profound tumour suppressive role in cancer by restraining the growth-promoting function of the transcriptional coactivator, YAP. We previously showed that the stem cell transcription factor Sox2 maintains cancer stem cells (CSCs) in osteosarcomas. We now report that in these tumours, Sox2 antagonizes the Hippo pathway by direct repression of two Hippo activators, Nf2 (Merlin) and WWC1 (Kibra), leading to exaggerated YAP function. Repression of Nf2, WWC1 and high YAP expression marks the CSC fraction of the tumor population, while the more differentiated fraction has high Nf2, high WWC1 and reduced YAP expression. YAP depletion sharply reduces CSCs and tumorigenicity of osteosarcomas. Thus, Sox2 interferes with the tumour-suppressive Hippo pathway to maintain CSCs in osteosarcomas. This Sox2-Hippo axis is conserved in other Sox2-dependent cancers such as glioblastomas. Disruption of YAP transcriptional activity could be a therapeutic strategy for Sox2-dependent tumours.
Transcriptional regulators Sox2 and YAP maintain expression of stemness genes in normal and cancerous cells. Here the authors show that, in osteosarcomas, Sox2 activates YAP by directly repressing transcription of its upstream negative regulators Nf2 and WWC1, promoting cancer cell stemness. |
| doi_str_mv | 10.1038/ncomms7411 |
| format | Article |
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Transcriptional regulators Sox2 and YAP maintain expression of stemness genes in normal and cancerous cells. Here the authors show that, in osteosarcomas, Sox2 activates YAP by directly repressing transcription of its upstream negative regulators Nf2 and WWC1, promoting cancer cell stemness.</description><identifier>ISSN: 2041-1723</identifier><identifier>EISSN: 2041-1723</identifier><identifier>DOI: 10.1038/ncomms7411</identifier><identifier>PMID: 25832504</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13 ; 13/100 ; 13/106 ; 13/109 ; 13/51 ; 13/89 ; 13/95 ; 14 ; 14/34 ; 14/63 ; 631/45/612/822 ; 631/67/1344 ; 631/67/71 ; 631/80/83/2360 ; 96 ; 96/100 ; Adaptor Proteins, Signal Transducing - genetics ; Adaptor Proteins, Signal Transducing - metabolism ; Cell Line, Tumor ; Gene Expression Regulation, Neoplastic ; Glioblastoma - genetics ; Glioblastoma - metabolism ; Humanities and Social Sciences ; Humans ; Intracellular Signaling Peptides and Proteins - genetics ; Intracellular Signaling Peptides and Proteins - metabolism ; multidisciplinary ; Neoplastic Stem Cells - metabolism ; Neurofibromin 2 - genetics ; Neurofibromin 2 - metabolism ; Osteosarcoma - genetics ; Osteosarcoma - metabolism ; Phosphoproteins - genetics ; Phosphoproteins - metabolism ; Protein-Serine-Threonine Kinases - genetics ; Protein-Serine-Threonine Kinases - metabolism ; Real-Time Polymerase Chain Reaction ; RNA, Messenger - metabolism ; Science ; Science (multidisciplinary) ; Signal Transduction ; SOXB1 Transcription Factors - genetics ; SOXB1 Transcription Factors - metabolism ; Transcription Factors</subject><ispartof>Nature communications, 2015-04, Vol.6 (1), p.6411-6411, Article 6411</ispartof><rights>Springer Nature Limited 2015</rights><rights>Copyright Nature Publishing Group Apr 2015</rights><rights>2015 Macmillan Publishers Limited. All rights reserved. 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c508t-6aac578d2798246349e8a2c2770a040095285aff4a5eddbb76ddb9582f2f85513</citedby><cites>FETCH-LOGICAL-c508t-6aac578d2798246349e8a2c2770a040095285aff4a5eddbb76ddb9582f2f85513</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4429898/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4429898/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,860,881,27901,27902,41096,42165,51551,53766,53768</link.rule.ids><linktorsrc>$$Uhttps://doi.org/10.1038/ncomms7411$$EView_record_in_Springer_Nature$$FView_record_in_$$GSpringer_Nature</linktorsrc><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25832504$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Basu-Roy, Upal</creatorcontrib><creatorcontrib>Bayin, N. Sumru</creatorcontrib><creatorcontrib>Rattanakorn, Kirk</creatorcontrib><creatorcontrib>Han, Eugenia</creatorcontrib><creatorcontrib>Placantonakis, Dimitris G.</creatorcontrib><creatorcontrib>Mansukhani, Alka</creatorcontrib><creatorcontrib>Basilico, Claudio</creatorcontrib><title>Sox2 antagonizes the Hippo pathway to maintain stemness in cancer cells</title><title>Nature communications</title><addtitle>Nat Commun</addtitle><addtitle>Nat Commun</addtitle><description>The repressive Hippo pathway has a profound tumour suppressive role in cancer by restraining the growth-promoting function of the transcriptional coactivator, YAP. We previously showed that the stem cell transcription factor Sox2 maintains cancer stem cells (CSCs) in osteosarcomas. We now report that in these tumours, Sox2 antagonizes the Hippo pathway by direct repression of two Hippo activators, Nf2 (Merlin) and WWC1 (Kibra), leading to exaggerated YAP function. Repression of Nf2, WWC1 and high YAP expression marks the CSC fraction of the tumor population, while the more differentiated fraction has high Nf2, high WWC1 and reduced YAP expression. YAP depletion sharply reduces CSCs and tumorigenicity of osteosarcomas. Thus, Sox2 interferes with the tumour-suppressive Hippo pathway to maintain CSCs in osteosarcomas. This Sox2-Hippo axis is conserved in other Sox2-dependent cancers such as glioblastomas. Disruption of YAP transcriptional activity could be a therapeutic strategy for Sox2-dependent tumours.
Transcriptional regulators Sox2 and YAP maintain expression of stemness genes in normal and cancerous cells. Here the authors show that, in osteosarcomas, Sox2 activates YAP by directly repressing transcription of its upstream negative regulators Nf2 and WWC1, promoting cancer cell stemness.</description><subject>13</subject><subject>13/100</subject><subject>13/106</subject><subject>13/109</subject><subject>13/51</subject><subject>13/89</subject><subject>13/95</subject><subject>14</subject><subject>14/34</subject><subject>14/63</subject><subject>631/45/612/822</subject><subject>631/67/1344</subject><subject>631/67/71</subject><subject>631/80/83/2360</subject><subject>96</subject><subject>96/100</subject><subject>Adaptor Proteins, Signal Transducing - genetics</subject><subject>Adaptor Proteins, Signal Transducing - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Glioblastoma - genetics</subject><subject>Glioblastoma - metabolism</subject><subject>Humanities and Social Sciences</subject><subject>Humans</subject><subject>Intracellular Signaling Peptides and Proteins - genetics</subject><subject>Intracellular Signaling Peptides and Proteins - metabolism</subject><subject>multidisciplinary</subject><subject>Neoplastic Stem Cells - metabolism</subject><subject>Neurofibromin 2 - genetics</subject><subject>Neurofibromin 2 - metabolism</subject><subject>Osteosarcoma - genetics</subject><subject>Osteosarcoma - metabolism</subject><subject>Phosphoproteins - genetics</subject><subject>Phosphoproteins - metabolism</subject><subject>Protein-Serine-Threonine Kinases - genetics</subject><subject>Protein-Serine-Threonine Kinases - metabolism</subject><subject>Real-Time Polymerase Chain Reaction</subject><subject>RNA, Messenger - metabolism</subject><subject>Science</subject><subject>Science (multidisciplinary)</subject><subject>Signal Transduction</subject><subject>SOXB1 Transcription Factors - genetics</subject><subject>SOXB1 Transcription Factors - metabolism</subject><subject>Transcription Factors</subject><issn>2041-1723</issn><issn>2041-1723</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>BENPR</sourceid><recordid>eNplkUFLAzEQhYMottRe_AES8CJKNckmu9mLIEVbQfCgnsM0zbZbusmabNX6601prVXnkBmYj5c3PISOKbmkJJFXVruqChmndA-1GeG0RzOW7O_MLdQNYUZiJTmVnB-iFhMyYYLwNho8uQ-GwTYwcbb8NAE3U4OHZV07XEMzfYclbhyuoIxIaXFoTGVNCDjOGqw2Hmszn4cjdFDAPJjupnfQy93tc3_Ye3gc3PdvHnpaENn0UgAtMjlmWS4ZTxOeGwlMsywjQDghuWBSQFFwEGY8Ho2yNL65kKxghRSCJh10vdatF6PKjLWxjYe5qn1ZgV8qB6X6vbHlVE3cm-Kc5TKXUeBsI-Dd68KERlVlWJ0A1rhFUDRNIyVzxiJ6-geduYW38bwVFf2TRCSROl9T2rsQvCm2ZihRq4jUT0QRPtm1v0W_A4nAxRoIcWUnxu_8-V_uC-m0m8Q</recordid><startdate>20150402</startdate><enddate>20150402</enddate><creator>Basu-Roy, Upal</creator><creator>Bayin, N. 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Sumru</au><au>Rattanakorn, Kirk</au><au>Han, Eugenia</au><au>Placantonakis, Dimitris G.</au><au>Mansukhani, Alka</au><au>Basilico, Claudio</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Sox2 antagonizes the Hippo pathway to maintain stemness in cancer cells</atitle><jtitle>Nature communications</jtitle><stitle>Nat Commun</stitle><addtitle>Nat Commun</addtitle><date>2015-04-02</date><risdate>2015</risdate><volume>6</volume><issue>1</issue><spage>6411</spage><epage>6411</epage><pages>6411-6411</pages><artnum>6411</artnum><issn>2041-1723</issn><eissn>2041-1723</eissn><abstract>The repressive Hippo pathway has a profound tumour suppressive role in cancer by restraining the growth-promoting function of the transcriptional coactivator, YAP. We previously showed that the stem cell transcription factor Sox2 maintains cancer stem cells (CSCs) in osteosarcomas. We now report that in these tumours, Sox2 antagonizes the Hippo pathway by direct repression of two Hippo activators, Nf2 (Merlin) and WWC1 (Kibra), leading to exaggerated YAP function. Repression of Nf2, WWC1 and high YAP expression marks the CSC fraction of the tumor population, while the more differentiated fraction has high Nf2, high WWC1 and reduced YAP expression. YAP depletion sharply reduces CSCs and tumorigenicity of osteosarcomas. Thus, Sox2 interferes with the tumour-suppressive Hippo pathway to maintain CSCs in osteosarcomas. This Sox2-Hippo axis is conserved in other Sox2-dependent cancers such as glioblastomas. Disruption of YAP transcriptional activity could be a therapeutic strategy for Sox2-dependent tumours.
Transcriptional regulators Sox2 and YAP maintain expression of stemness genes in normal and cancerous cells. Here the authors show that, in osteosarcomas, Sox2 activates YAP by directly repressing transcription of its upstream negative regulators Nf2 and WWC1, promoting cancer cell stemness.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>25832504</pmid><doi>10.1038/ncomms7411</doi><tpages>1</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | 13 13/100 13/106 13/109 13/51 13/89 13/95 14 14/34 14/63 631/45/612/822 631/67/1344 631/67/71 631/80/83/2360 96 96/100 Adaptor Proteins, Signal Transducing - genetics Adaptor Proteins, Signal Transducing - metabolism Cell Line, Tumor Gene Expression Regulation, Neoplastic Glioblastoma - genetics Glioblastoma - metabolism Humanities and Social Sciences Humans Intracellular Signaling Peptides and Proteins - genetics Intracellular Signaling Peptides and Proteins - metabolism multidisciplinary Neoplastic Stem Cells - metabolism Neurofibromin 2 - genetics Neurofibromin 2 - metabolism Osteosarcoma - genetics Osteosarcoma - metabolism Phosphoproteins - genetics Phosphoproteins - metabolism Protein-Serine-Threonine Kinases - genetics Protein-Serine-Threonine Kinases - metabolism Real-Time Polymerase Chain Reaction RNA, Messenger - metabolism Science Science (multidisciplinary) Signal Transduction SOXB1 Transcription Factors - genetics SOXB1 Transcription Factors - metabolism Transcription Factors |
| title | Sox2 antagonizes the Hippo pathway to maintain stemness in cancer cells |
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