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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">LSD1 destabilizes FBXW7 and abrogates FBXW7 functions independent of its demethylase activity</title><author><name sortKey="Lan, Huiyin" sort="Lan, Huiyin" uniqKey="Lan H" first="Huiyin" last="Lan">Huiyin Lan</name><affiliation><nlm:aff id="aff1">Cancer Institute of the Second Affiliated Hospital and Institute of Translational Medicine,<institution>Zhejiang University School of Medicine</institution>, 310029 Hangzhou,<country>China</country>;</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Division of Radiation and Cancer Biology, Department of Radiation Oncology,<institution>University of Michigan</institution>, Ann Arbor,<addr-line>MI</addr-line> 48109</nlm:aff></affiliation></author><author><name sortKey="Tan, Mingjia" sort="Tan, Mingjia" uniqKey="Tan M" first="Mingjia" last="Tan">Mingjia Tan</name><affiliation><nlm:aff id="aff2">Division of Radiation and Cancer Biology, Department of Radiation Oncology,<institution>University of Michigan</institution>, Ann Arbor,<addr-line>MI</addr-line> 48109</nlm:aff></affiliation></author><author><name sortKey="Zhang, Qiang" sort="Zhang, Qiang" uniqKey="Zhang Q" first="Qiang" last="Zhang">Qiang Zhang</name><affiliation><nlm:aff id="aff2">Division of Radiation and Cancer Biology, Department of Radiation Oncology,<institution>University of Michigan</institution>, Ann Arbor,<addr-line>MI</addr-line> 48109</nlm:aff></affiliation></author><author><name sortKey="Yang, Fei" sort="Yang, Fei" uniqKey="Yang F" first="Fei" last="Yang">Fei Yang</name><affiliation><nlm:aff id="aff1">Cancer Institute of the Second Affiliated Hospital and Institute of Translational Medicine,<institution>Zhejiang University School of Medicine</institution>, 310029 Hangzhou,<country>China</country>;</nlm:aff></affiliation></author><author><name sortKey="Wang, Siyuan" sort="Wang, Siyuan" uniqKey="Wang S" first="Siyuan" last="Wang">Siyuan Wang</name><affiliation><nlm:aff id="aff1">Cancer Institute of the Second Affiliated Hospital and Institute of Translational Medicine,<institution>Zhejiang University School of Medicine</institution>, 310029 Hangzhou,<country>China</country>;</nlm:aff></affiliation></author><author><name sortKey="Li, Hua" sort="Li, Hua" uniqKey="Li H" first="Hua" last="Li">Hua Li</name><affiliation><nlm:aff id="aff2">Division of Radiation and Cancer Biology, Department of Radiation Oncology,<institution>University of Michigan</institution>, Ann Arbor,<addr-line>MI</addr-line> 48109</nlm:aff></affiliation></author><author><name sortKey="Xiong, Xiufang" sort="Xiong, Xiufang" uniqKey="Xiong X" first="Xiufang" last="Xiong">Xiufang Xiong</name><affiliation><nlm:aff id="aff1">Cancer Institute of the Second Affiliated Hospital and Institute of Translational Medicine,<institution>Zhejiang University School of Medicine</institution>, 310029 Hangzhou,<country>China</country>;</nlm:aff></affiliation></author><author><name sortKey="Sun, Yi" sort="Sun, Yi" uniqKey="Sun Y" first="Yi" last="Sun">Yi Sun</name><affiliation><nlm:aff id="aff1">Cancer Institute of the Second Affiliated Hospital and Institute of Translational Medicine,<institution>Zhejiang University School of Medicine</institution>, 310029 Hangzhou,<country>China</country>;</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Division of Radiation and Cancer Biology, Department of Radiation Oncology,<institution>University of Michigan</institution>, Ann Arbor,<addr-line>MI</addr-line> 48109</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">31152129</idno><idno type="pmc">6589684</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589684</idno><idno type="RBID">PMC:6589684</idno><idno type="doi">10.1073/pnas.1902012116</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000374</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000374</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">LSD1 destabilizes FBXW7 and abrogates FBXW7 functions independent of its demethylase activity</title><author><name sortKey="Lan, Huiyin" sort="Lan, Huiyin" uniqKey="Lan H" first="Huiyin" last="Lan">Huiyin Lan</name><affiliation><nlm:aff id="aff1">Cancer Institute of the Second Affiliated Hospital and Institute of Translational Medicine,<institution>Zhejiang University School of Medicine</institution>, 310029 Hangzhou,<country>China</country>;</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Division of Radiation and Cancer Biology, Department of Radiation Oncology,<institution>University of Michigan</institution>, Ann Arbor,<addr-line>MI</addr-line> 48109</nlm:aff></affiliation></author><author><name sortKey="Tan, Mingjia" sort="Tan, Mingjia" uniqKey="Tan M" first="Mingjia" last="Tan">Mingjia Tan</name><affiliation><nlm:aff id="aff2">Division of Radiation and Cancer Biology, Department of Radiation Oncology,<institution>University of Michigan</institution>, Ann Arbor,<addr-line>MI</addr-line> 48109</nlm:aff></affiliation></author><author><name sortKey="Zhang, Qiang" sort="Zhang, Qiang" uniqKey="Zhang Q" first="Qiang" last="Zhang">Qiang Zhang</name><affiliation><nlm:aff id="aff2">Division of Radiation and Cancer Biology, Department of Radiation Oncology,<institution>University of Michigan</institution>, Ann Arbor,<addr-line>MI</addr-line> 48109</nlm:aff></affiliation></author><author><name sortKey="Yang, Fei" sort="Yang, Fei" uniqKey="Yang F" first="Fei" last="Yang">Fei Yang</name><affiliation><nlm:aff id="aff1">Cancer Institute of the Second Affiliated Hospital and Institute of Translational Medicine,<institution>Zhejiang University School of Medicine</institution>, 310029 Hangzhou,<country>China</country>;</nlm:aff></affiliation></author><author><name sortKey="Wang, Siyuan" sort="Wang, Siyuan" uniqKey="Wang S" first="Siyuan" last="Wang">Siyuan Wang</name><affiliation><nlm:aff id="aff1">Cancer Institute of the Second Affiliated Hospital and Institute of Translational Medicine,<institution>Zhejiang University School of Medicine</institution>, 310029 Hangzhou,<country>China</country>;</nlm:aff></affiliation></author><author><name sortKey="Li, Hua" sort="Li, Hua" uniqKey="Li H" first="Hua" last="Li">Hua Li</name><affiliation><nlm:aff id="aff2">Division of Radiation and Cancer Biology, Department of Radiation Oncology,<institution>University of Michigan</institution>, Ann Arbor,<addr-line>MI</addr-line> 48109</nlm:aff></affiliation></author><author><name sortKey="Xiong, Xiufang" sort="Xiong, Xiufang" uniqKey="Xiong X" first="Xiufang" last="Xiong">Xiufang Xiong</name><affiliation><nlm:aff id="aff1">Cancer Institute of the Second Affiliated Hospital and Institute of Translational Medicine,<institution>Zhejiang University School of Medicine</institution>, 310029 Hangzhou,<country>China</country>;</nlm:aff></affiliation></author><author><name sortKey="Sun, Yi" sort="Sun, Yi" uniqKey="Sun Y" first="Yi" last="Sun">Yi Sun</name><affiliation><nlm:aff id="aff1">Cancer Institute of the Second Affiliated Hospital and Institute of Translational Medicine,<institution>Zhejiang University School of Medicine</institution>, 310029 Hangzhou,<country>China</country>;</nlm:aff></affiliation><affiliation><nlm:aff id="aff2">Division of Radiation and Cancer Biology, Department of Radiation Oncology,<institution>University of Michigan</institution>, Ann Arbor,<addr-line>MI</addr-line> 48109</nlm:aff></affiliation></author></analytic><series><title level="j">Proceedings of the National Academy of Sciences of the United States of America</title><idno type="ISSN">0027-8424</idno><idno type="eISSN">1091-6490</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Significance</title><p>FBXW7 is a typical tumor suppressor by targeting many oncoproteins for ubiquitylation and degradation, whereas LSD1 has oncogenic activity. Whether and how FBXW7 and LSD1 interact, with what biological consequence, are unknown. Here, we report that LSD1 is a pseudosubstrate of FBXW7. Upon binding with FBXW7, LSD1, instead of being degraded, disrupts FBXW7 dimerization and promotes FBXW7 self-ubiquitylation and degradation via proteasome and lysosomal pathways in a manner independent of its demethylase activity. As such, LSD1 abrogates biological functions of FBXW7 in growth suppression, nonhomologous end-joining repair, and radioprotection. Our study reveals a novel oncogenic mechanism of LSD1 by targeting FBXW7 and provides a sound strategy to reactivate FBXW7 by PROTAC-based LSD1 degradation in human cancers harboring wild-type FBXW7 with overexpressed LSD1.</p></div></front></TEI><pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Proc Natl Acad Sci U S A</journal-id><journal-id journal-id-type="iso-abbrev">Proc. Natl. Acad. Sci. U.S.A</journal-id><journal-id journal-id-type="hwp">pnas</journal-id><journal-id journal-id-type="pmc">pnas</journal-id><journal-id journal-id-type="publisher-id">PNAS</journal-id><journal-title-group><journal-title>Proceedings of the National Academy of Sciences of the United States of America</journal-title></journal-title-group><issn pub-type="ppub">0027-8424</issn><issn pub-type="epub">1091-6490</issn><publisher><publisher-name>National Academy of Sciences</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">31152129</article-id><article-id pub-id-type="pmc">6589684</article-id><article-id pub-id-type="publisher-id">201902012</article-id><article-id pub-id-type="doi">10.1073/pnas.1902012116</article-id><article-categories><subj-group subj-group-type="heading"><subject>PNAS Plus</subject></subj-group><subj-group subj-group-type="heading"><subject>Biological Sciences</subject><subj-group><subject>Cell Biology</subject></subj-group></subj-group><series-title>PNAS Plus</series-title></article-categories><title-group><article-title>LSD1 destabilizes FBXW7 and abrogates FBXW7 functions independent of its demethylase activity</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Lan</surname><given-names>Huiyin</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Tan</surname><given-names>Mingjia</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Zhang</surname><given-names>Qiang</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Yang</surname><given-names>Fei</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Siyuan</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Li</surname><given-names>Hua</given-names></name><xref ref-type="aff" rid="aff2"><sup>b</sup></xref></contrib><contrib contrib-type="author"><name><surname>Xiong</surname><given-names>Xiufang</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref></contrib><contrib contrib-type="author"><name><surname>Sun</surname><given-names>Yi</given-names></name><xref ref-type="aff" rid="aff1"><sup>a</sup></xref><xref ref-type="aff" rid="aff2"><sup>b</sup></xref><xref ref-type="corresp" rid="cor1"><sup>1</sup></xref></contrib><aff id="aff1"><sup>a</sup>Cancer Institute of the Second Affiliated Hospital and Institute of Translational Medicine,<institution>Zhejiang University School of Medicine</institution>, 310029 Hangzhou,<country>China</country>;</aff><aff id="aff2"><sup>b</sup>Division of Radiation and Cancer Biology, Department of Radiation Oncology,<institution>University of Michigan</institution>, Ann Arbor,<addr-line>MI</addr-line> 48109</aff></contrib-group><author-notes><corresp id="cor1"><sup>1</sup>To whom correspondence may be addressed. Email: <email>sunyi@umich.edu</email>.</corresp><fn fn-type="edited-by"><p>Edited by Michele Pagano, HHMI and NYU School of Medicine, New York, NY, and accepted by Editorial Board Member Carol Prives April 30, 2019 (received for review February 3, 2019)</p></fn><fn fn-type="con"><p>Author contributions: H. Lan and Y.S. designed research; H. Lan, M.T., Q.Z., and S.W. performed research; F.Y., H. Li, X.X., and Y.S. contributed new reagents/analytic tools; H. Lan and Y.S. analyzed data; and H. Lan and Y.S. wrote the paper.</p></fn><fn fn-type="COI-statement"><p>The authors declare no conflict of interest.</p></fn></author-notes><pub-date pub-type="ppub"><day>18</day><month>6</month><year>2019</year></pub-date><pub-date pub-type="epub"><day>31</day><month>5</month><year>2019</year></pub-date><volume>116</volume><issue>25</issue><fpage>12311</fpage><lpage>12320</lpage><permissions><copyright-year>2019</copyright-year><license><ali:license_ref specific-use="vor">https://www.pnas.org/site/aboutpnas/licenses.xhtml</ali:license_ref><license-p>Published under the <ext-link ext-link-type="uri" xlink:href="https://www.pnas.org/site/aboutpnas/licenses.xhtml">PNAS license</ext-link>.</license-p></license></permissions><self-uri xlink:title="pdf" xlink:href="pnas.201902012.pdf"></self-uri><abstract abstract-type="executive-summary"><title>Significance</title><p>FBXW7 is a typical tumor suppressor by targeting many oncoproteins for ubiquitylation and degradation, whereas LSD1 has oncogenic activity. Whether and how FBXW7 and LSD1 interact, with what biological consequence, are unknown. Here, we report that LSD1 is a pseudosubstrate of FBXW7. Upon binding with FBXW7, LSD1, instead of being degraded, disrupts FBXW7 dimerization and promotes FBXW7 self-ubiquitylation and degradation via proteasome and lysosomal pathways in a manner independent of its demethylase activity. As such, LSD1 abrogates biological functions of FBXW7 in growth suppression, nonhomologous end-joining repair, and radioprotection. Our study reveals a novel oncogenic mechanism of LSD1 by targeting FBXW7 and provides a sound strategy to reactivate FBXW7 by PROTAC-based LSD1 degradation in human cancers harboring wild-type FBXW7 with overexpressed LSD1.</p></abstract><abstract><p>FBXW7 acts as a typical tumor suppressor, with loss-of-function alterations in human cancers, by promoting ubiquitylation and degradation of many oncoproteins. Lysine-specific demethylase 1 (LSD1) is a well-characterized histone demethylase. Whether LSD1 has demethylase-independent activity remains elusive. Here we report that LSD1 directly binds to FBXW7 to destabilize FBXW7 independent of its demethylase activity. Specifically, LSD1 is a pseudosubstrate of FBXW7 and LSD1–FBXW7 binding does not trigger LSD1 ubiquitylation, but instead promotes FBXW7 self-ubiquitylation by preventing FBXW7 dimerization. The self-ubiquitylated FBXW7 is subjected to degradation by proteasome as well as lysosome in a manner dependent on autophagy protein p62/SQSTM1. Biologically, LSD1 destabilizes FBXW7 to abrogate its functions in growth suppression, nonhomologous end-joining repair, and radioprotection. Collectively, our study revealed a previously unknown activity of LSD1, which likely contributes to its oncogenic function. Targeting LSD1 protein, not only its demethylase activity, might be a unique approach for LSD1-based drug discovery for anticancer application.</p></abstract><kwd-group><kwd>degradation</kwd><kwd>DNA damage repair</kwd><kwd>SCF E3 ligase</kwd><kwd>ubiquitylation</kwd></kwd-group><funding-group><award-group id="gs1"><funding-source id="sp1">HHS | NIH | National Cancer Institute (NCI)<named-content content-type="funder-id">100000054</named-content></funding-source><award-id rid="sp1">CA156744</award-id><principal-award-recipient>Yi Sun</principal-award-recipient></award-group></funding-group><counts><page-count count="10"></page-count></counts></article-meta></front></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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