The Role of ZNF143 in Breast Cancer Cell Survival Through the NAD(P)H Quinone Dehydrogenase 1–p53–Beclin1 Axis Under Metabolic Stress
Identifieur interne : 000319 ( Pmc/Checkpoint ); précédent : 000318; suivant : 000320The Role of ZNF143 in Breast Cancer Cell Survival Through the NAD(P)H Quinone Dehydrogenase 1–p53–Beclin1 Axis Under Metabolic Stress
Auteurs : A Rome Paek ; Ji Young Mun ; Mun Jeong Jo ; Hyosun Choi ; Yun Jeong Lee ; Heesun Cheong [Corée du Sud] ; Jae Kyung Myung ; Dong Wan Hong ; Jongkeun Park ; Kyung-Hee Kim ; Hye Jin YouSource :
- Cells [ 2073-4409 ] ; 2019.
Abstract
Autophagy is a cellular process that disrupts and uses unnecessary or malfunctioning components for cellular homeostasis. Evidence has shown a role for autophagy in tumor cell survival, but the molecular determinants that define sensitivity against autophagic regulation in cancers are not clear. Importantly, we found that breast cancer cells with low expression levels of a zinc-finger protein, ZNF143 (MCF7 sh-ZNF143), showed better survival than control cells (MCF7 sh-Control) under starvation, which was compromised with chloroquine, an autophagy inhibitor. In addition, there were more autophagic vesicles in MCF7 sh-ZNF143 cells than in MCF7 sh-Control cells, and proteins related with the autophagic process, such as Beclin1, p62, and ATGs, were altered in cells with less ZNF143. ZNF143 knockdown affected the stability of p53, which showed a dependence on MG132, a proteasome inhibitor. Data from proteome profiling in breast cancer cells with less ZNF143 suggest a role of NAD(P)H quinone dehydrogenase 1(NQO1) for p53 stability. Taken together, we showed that a subset of breast cancer cells with low expression of ZNF143 might exhibit better survival via an autophagic process by regulating the p53–Beclin1 axis, corroborating the necessity of blocking autophagy for the best therapy.
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DOI: 10.3390/cells8040296
PubMed: 30935019
PubMed Central: 6523662
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">The Role of ZNF143 in Breast Cancer Cell Survival Through the NAD(P)H Quinone Dehydrogenase 1–p53–Beclin1 Axis Under Metabolic Stress</title><author><name sortKey="Paek, A Rome" sort="Paek, A Rome" uniqKey="Paek A" first="A Rome" last="Paek">A Rome Paek</name><affiliation><nlm:aff id="af1-cells-08-00296">Division of Translational Science, Research Institute, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi 10408, Korea;<email>arpaek@ncc.re.kr</email> (A.R.P.);<email>cromanyon@naver.com</email> (M.J.J.)</nlm:aff></affiliation></author><author><name sortKey="Mun, Ji Young" sort="Mun, Ji Young" uniqKey="Mun J" first="Ji Young" last="Mun">Ji Young Mun</name><affiliation><nlm:aff id="af2-cells-08-00296">Department of Structure and Function of Neural Network, Korea Brain Research Institute, Daegu 41068, Korea;<email>jymun@kbri.re.kr</email></nlm:aff></affiliation></author><author><name sortKey="Jo, Mun Jeong" sort="Jo, Mun Jeong" uniqKey="Jo M" first="Mun Jeong" last="Jo">Mun Jeong Jo</name><affiliation><nlm:aff id="af1-cells-08-00296">Division of Translational Science, Research Institute, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi 10408, Korea;<email>arpaek@ncc.re.kr</email> (A.R.P.);<email>cromanyon@naver.com</email> (M.J.J.)</nlm:aff></affiliation></author><author><name sortKey="Choi, Hyosun" sort="Choi, Hyosun" uniqKey="Choi H" first="Hyosun" last="Choi">Hyosun Choi</name><affiliation><nlm:aff id="af3-cells-08-00296">BK21 Plus Program, Department of Senior Healthcare, Graduate School, Eulji University, Daejeon 34824, Korea;<email>hyokchoi0123@gmail.com</email></nlm:aff></affiliation></author><author><name sortKey="Lee, Yun Jeong" sort="Lee, Yun Jeong" uniqKey="Lee Y" first="Yun Jeong" last="Lee">Yun Jeong Lee</name><affiliation><nlm:aff id="af4-cells-08-00296">Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi 10408, Korea;<email>74424@ncc.re.kr</email> (Y.J.L.);<email>heesunch@ncc.re.kr</email> (H.C.);<email>jkmyung@ncc.re.kr</email> (J.K.M.)</nlm:aff></affiliation></author><author><name sortKey="Cheong, Heesun" sort="Cheong, Heesun" uniqKey="Cheong H" first="Heesun" last="Cheong">Heesun Cheong</name><affiliation><nlm:aff id="af4-cells-08-00296">Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi 10408, Korea;<email>74424@ncc.re.kr</email> (Y.J.L.);<email>heesunch@ncc.re.kr</email> (H.C.);<email>jkmyung@ncc.re.kr</email> (J.K.M.)</nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af5-cells-08-00296">Division of Cancer Biology, Research Institute, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi 10408, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Division of Cancer Biology, Research Institute, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi 10408</wicri:regionArea><wicri:noRegion>Gyeonggi 10408</wicri:noRegion></affiliation></author><author><name sortKey="Myung, Jae Kyung" sort="Myung, Jae Kyung" uniqKey="Myung J" first="Jae Kyung" last="Myung">Jae Kyung Myung</name><affiliation><nlm:aff id="af4-cells-08-00296">Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi 10408, Korea;<email>74424@ncc.re.kr</email> (Y.J.L.);<email>heesunch@ncc.re.kr</email> (H.C.);<email>jkmyung@ncc.re.kr</email> (J.K.M.)</nlm:aff></affiliation></author><author><name sortKey="Hong, Dong Wan" sort="Hong, Dong Wan" uniqKey="Hong D" first="Dong Wan" last="Hong">Dong Wan Hong</name><affiliation><nlm:aff id="af6-cells-08-00296">Bioinformatics Analysis Team, Research Institute, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi 10408, Korea;<email>dwhong@ncc.re.kr</email> (D.W.H.);<email>jkpark@ncc.re.kr</email> (J.P.)</nlm:aff></affiliation></author><author><name sortKey="Park, Jongkeun" sort="Park, Jongkeun" uniqKey="Park J" first="Jongkeun" last="Park">Jongkeun Park</name><affiliation><nlm:aff id="af6-cells-08-00296">Bioinformatics Analysis Team, Research Institute, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi 10408, Korea;<email>dwhong@ncc.re.kr</email> (D.W.H.);<email>jkpark@ncc.re.kr</email> (J.P.)</nlm:aff></affiliation></author><author><name sortKey="Kim, Kyung Hee" sort="Kim, Kyung Hee" uniqKey="Kim K" first="Kyung-Hee" last="Kim">Kyung-Hee Kim</name><affiliation><nlm:aff id="af7-cells-08-00296">Proteogenomic Analysis Team, Research Institute, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi 10408, Korea;<email>kyunghee@ncc.re.kr</email></nlm:aff></affiliation></author><author><name sortKey="You, Hye Jin" sort="You, Hye Jin" uniqKey="You H" first="Hye Jin" last="You">Hye Jin You</name><affiliation><nlm:aff id="af1-cells-08-00296">Division of Translational Science, Research Institute, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi 10408, Korea;<email>arpaek@ncc.re.kr</email> (A.R.P.);<email>cromanyon@naver.com</email> (M.J.J.)</nlm:aff></affiliation><affiliation><nlm:aff id="af4-cells-08-00296">Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi 10408, Korea;<email>74424@ncc.re.kr</email> (Y.J.L.);<email>heesunch@ncc.re.kr</email> (H.C.);<email>jkmyung@ncc.re.kr</email> (J.K.M.)</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">30935019</idno><idno type="pmc">6523662</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6523662</idno><idno type="RBID">PMC:6523662</idno><idno type="doi">10.3390/cells8040296</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">000471</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">000471</idno><idno type="wicri:Area/Pmc/Curation">000471</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">000471</idno><idno type="wicri:Area/Pmc/Checkpoint">000319</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Checkpoint">000319</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">The Role of ZNF143 in Breast Cancer Cell Survival Through the NAD(P)H Quinone Dehydrogenase 1–p53–Beclin1 Axis Under Metabolic Stress</title><author><name sortKey="Paek, A Rome" sort="Paek, A Rome" uniqKey="Paek A" first="A Rome" last="Paek">A Rome Paek</name><affiliation><nlm:aff id="af1-cells-08-00296">Division of Translational Science, Research Institute, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi 10408, Korea;<email>arpaek@ncc.re.kr</email> (A.R.P.);<email>cromanyon@naver.com</email> (M.J.J.)</nlm:aff></affiliation></author><author><name sortKey="Mun, Ji Young" sort="Mun, Ji Young" uniqKey="Mun J" first="Ji Young" last="Mun">Ji Young Mun</name><affiliation><nlm:aff id="af2-cells-08-00296">Department of Structure and Function of Neural Network, Korea Brain Research Institute, Daegu 41068, Korea;<email>jymun@kbri.re.kr</email></nlm:aff></affiliation></author><author><name sortKey="Jo, Mun Jeong" sort="Jo, Mun Jeong" uniqKey="Jo M" first="Mun Jeong" last="Jo">Mun Jeong Jo</name><affiliation><nlm:aff id="af1-cells-08-00296">Division of Translational Science, Research Institute, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi 10408, Korea;<email>arpaek@ncc.re.kr</email> (A.R.P.);<email>cromanyon@naver.com</email> (M.J.J.)</nlm:aff></affiliation></author><author><name sortKey="Choi, Hyosun" sort="Choi, Hyosun" uniqKey="Choi H" first="Hyosun" last="Choi">Hyosun Choi</name><affiliation><nlm:aff id="af3-cells-08-00296">BK21 Plus Program, Department of Senior Healthcare, Graduate School, Eulji University, Daejeon 34824, Korea;<email>hyokchoi0123@gmail.com</email></nlm:aff></affiliation></author><author><name sortKey="Lee, Yun Jeong" sort="Lee, Yun Jeong" uniqKey="Lee Y" first="Yun Jeong" last="Lee">Yun Jeong Lee</name><affiliation><nlm:aff id="af4-cells-08-00296">Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi 10408, Korea;<email>74424@ncc.re.kr</email> (Y.J.L.);<email>heesunch@ncc.re.kr</email> (H.C.);<email>jkmyung@ncc.re.kr</email> (J.K.M.)</nlm:aff></affiliation></author><author><name sortKey="Cheong, Heesun" sort="Cheong, Heesun" uniqKey="Cheong H" first="Heesun" last="Cheong">Heesun Cheong</name><affiliation><nlm:aff id="af4-cells-08-00296">Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi 10408, Korea;<email>74424@ncc.re.kr</email> (Y.J.L.);<email>heesunch@ncc.re.kr</email> (H.C.);<email>jkmyung@ncc.re.kr</email> (J.K.M.)</nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af5-cells-08-00296">Division of Cancer Biology, Research Institute, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi 10408, Korea</nlm:aff><country xml:lang="fr">Corée du Sud</country><wicri:regionArea>Division of Cancer Biology, Research Institute, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi 10408</wicri:regionArea><wicri:noRegion>Gyeonggi 10408</wicri:noRegion></affiliation></author><author><name sortKey="Myung, Jae Kyung" sort="Myung, Jae Kyung" uniqKey="Myung J" first="Jae Kyung" last="Myung">Jae Kyung Myung</name><affiliation><nlm:aff id="af4-cells-08-00296">Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi 10408, Korea;<email>74424@ncc.re.kr</email> (Y.J.L.);<email>heesunch@ncc.re.kr</email> (H.C.);<email>jkmyung@ncc.re.kr</email> (J.K.M.)</nlm:aff></affiliation></author><author><name sortKey="Hong, Dong Wan" sort="Hong, Dong Wan" uniqKey="Hong D" first="Dong Wan" last="Hong">Dong Wan Hong</name><affiliation><nlm:aff id="af6-cells-08-00296">Bioinformatics Analysis Team, Research Institute, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi 10408, Korea;<email>dwhong@ncc.re.kr</email> (D.W.H.);<email>jkpark@ncc.re.kr</email> (J.P.)</nlm:aff></affiliation></author><author><name sortKey="Park, Jongkeun" sort="Park, Jongkeun" uniqKey="Park J" first="Jongkeun" last="Park">Jongkeun Park</name><affiliation><nlm:aff id="af6-cells-08-00296">Bioinformatics Analysis Team, Research Institute, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi 10408, Korea;<email>dwhong@ncc.re.kr</email> (D.W.H.);<email>jkpark@ncc.re.kr</email> (J.P.)</nlm:aff></affiliation></author><author><name sortKey="Kim, Kyung Hee" sort="Kim, Kyung Hee" uniqKey="Kim K" first="Kyung-Hee" last="Kim">Kyung-Hee Kim</name><affiliation><nlm:aff id="af7-cells-08-00296">Proteogenomic Analysis Team, Research Institute, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi 10408, Korea;<email>kyunghee@ncc.re.kr</email></nlm:aff></affiliation></author><author><name sortKey="You, Hye Jin" sort="You, Hye Jin" uniqKey="You H" first="Hye Jin" last="You">Hye Jin You</name><affiliation><nlm:aff id="af1-cells-08-00296">Division of Translational Science, Research Institute, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi 10408, Korea;<email>arpaek@ncc.re.kr</email> (A.R.P.);<email>cromanyon@naver.com</email> (M.J.J.)</nlm:aff></affiliation><affiliation><nlm:aff id="af4-cells-08-00296">Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi 10408, Korea;<email>74424@ncc.re.kr</email> (Y.J.L.);<email>heesunch@ncc.re.kr</email> (H.C.);<email>jkmyung@ncc.re.kr</email> (J.K.M.)</nlm:aff></affiliation></author></analytic><series><title level="j">Cells</title><idno type="eISSN">2073-4409</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>Autophagy is a cellular process that disrupts and uses unnecessary or malfunctioning components for cellular homeostasis. Evidence has shown a role for autophagy in tumor cell survival, but the molecular determinants that define sensitivity against autophagic regulation in cancers are not clear. Importantly, we found that breast cancer cells with low expression levels of a zinc-finger protein, ZNF143 (MCF7 sh-ZNF143), showed better survival than control cells (MCF7 sh-Control) under starvation, which was compromised with chloroquine, an autophagy inhibitor. In addition, there were more autophagic vesicles in MCF7 sh-ZNF143 cells than in MCF7 sh-Control cells, and proteins related with the autophagic process, such as Beclin1, p62, and ATGs, were altered in cells with less ZNF143. ZNF143 knockdown affected the stability of p53, which showed a dependence on MG132, a proteasome inhibitor. Data from proteome profiling in breast cancer cells with less ZNF143 suggest a role of NAD(P)H quinone dehydrogenase 1(NQO1) for p53 stability. Taken together, we showed that a subset of breast cancer cells with low expression of ZNF143 might exhibit better survival via an autophagic process by regulating the p53–Beclin1 axis, corroborating the necessity of blocking autophagy for the best therapy.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Heng, Y J" uniqKey="Heng Y">Y.J. Heng</name></author><author><name sortKey="Lester, S C" uniqKey="Lester S">S.C. Lester</name></author><author><name sortKey="Tse, G M" uniqKey="Tse G">G.M. Tse</name></author><author><name sortKey="Factor, R E" uniqKey="Factor R">R.E. Factor</name></author><author><name sortKey="Allison, K H" uniqKey="Allison K">K.H. Allison</name></author><author><name sortKey="Collins, L C" uniqKey="Collins L">L.C. Collins</name></author><author><name sortKey="Chen, Y Y" uniqKey="Chen Y">Y.Y. Chen</name></author><author><name sortKey="Jensen, K C" uniqKey="Jensen K">K.C. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Cells</journal-id><journal-id journal-id-type="iso-abbrev">Cells</journal-id><journal-id journal-id-type="publisher-id">cells</journal-id><journal-title-group><journal-title>Cells</journal-title></journal-title-group><issn pub-type="epub">2073-4409</issn><publisher><publisher-name>MDPI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">30935019</article-id><article-id pub-id-type="pmc">6523662</article-id><article-id pub-id-type="doi">10.3390/cells8040296</article-id><article-id pub-id-type="publisher-id">cells-08-00296</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>The Role of ZNF143 in Breast Cancer Cell Survival Through the NAD(P)H Quinone Dehydrogenase 1–p53–Beclin1 Axis Under Metabolic Stress</article-title></title-group><contrib-group><contrib contrib-type="author"><name><surname>Paek</surname><given-names>A Rome</given-names></name><xref ref-type="aff" rid="af1-cells-08-00296">1</xref></contrib><contrib contrib-type="author"><name><surname>Mun</surname><given-names>Ji Young</given-names></name><xref ref-type="aff" rid="af2-cells-08-00296">2</xref></contrib><contrib contrib-type="author"><name><surname>Jo</surname><given-names>Mun Jeong</given-names></name><xref ref-type="aff" rid="af1-cells-08-00296">1</xref></contrib><contrib contrib-type="author"><name><surname>Choi</surname><given-names>Hyosun</given-names></name><xref ref-type="aff" rid="af3-cells-08-00296">3</xref></contrib><contrib contrib-type="author"><name><surname>Lee</surname><given-names>Yun Jeong</given-names></name><xref ref-type="aff" rid="af4-cells-08-00296">4</xref></contrib><contrib contrib-type="author"><name><surname>Cheong</surname><given-names>Heesun</given-names></name><xref ref-type="aff" rid="af4-cells-08-00296">4</xref><xref ref-type="aff" rid="af5-cells-08-00296">5</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0003-2276-4143</contrib-id><name><surname>Myung</surname><given-names>Jae Kyung</given-names></name><xref ref-type="aff" rid="af4-cells-08-00296">4</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-7816-1299</contrib-id><name><surname>Hong</surname><given-names>Dong Wan</given-names></name><xref ref-type="aff" rid="af6-cells-08-00296">6</xref></contrib><contrib contrib-type="author"><name><surname>Park</surname><given-names>Jongkeun</given-names></name><xref ref-type="aff" rid="af6-cells-08-00296">6</xref></contrib><contrib contrib-type="author"><name><surname>Kim</surname><given-names>Kyung-Hee</given-names></name><xref ref-type="aff" rid="af7-cells-08-00296">7</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0001-5566-5171</contrib-id><name><surname>You</surname><given-names>Hye Jin</given-names></name><xref ref-type="aff" rid="af1-cells-08-00296">1</xref><xref ref-type="aff" rid="af4-cells-08-00296">4</xref><xref rid="c1-cells-08-00296" ref-type="corresp">*</xref></contrib></contrib-group><aff id="af1-cells-08-00296"><label>1</label>Division of Translational Science, Research Institute, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi 10408, Korea;<email>arpaek@ncc.re.kr</email> (A.R.P.);<email>cromanyon@naver.com</email> (M.J.J.)</aff><aff id="af2-cells-08-00296"><label>2</label>Department of Structure and Function of Neural Network, Korea Brain Research Institute, Daegu 41068, Korea;<email>jymun@kbri.re.kr</email></aff><aff id="af3-cells-08-00296"><label>3</label>BK21 Plus Program, Department of Senior Healthcare, Graduate School, Eulji University, Daejeon 34824, Korea;<email>hyokchoi0123@gmail.com</email></aff><aff id="af4-cells-08-00296"><label>4</label>Department of Cancer Biomedical Science, National Cancer Center Graduate School of Cancer Science and Policy, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi 10408, Korea;<email>74424@ncc.re.kr</email> (Y.J.L.);<email>heesunch@ncc.re.kr</email> (H.C.);<email>jkmyung@ncc.re.kr</email> (J.K.M.)</aff><aff id="af5-cells-08-00296"><label>5</label>Division of Cancer Biology, Research Institute, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi 10408, Korea</aff><aff id="af6-cells-08-00296"><label>6</label>Bioinformatics Analysis Team, Research Institute, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi 10408, Korea;<email>dwhong@ncc.re.kr</email> (D.W.H.);<email>jkpark@ncc.re.kr</email> (J.P.)</aff><aff id="af7-cells-08-00296"><label>7</label>Proteogenomic Analysis Team, Research Institute, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang, Gyeonggi 10408, Korea;<email>kyunghee@ncc.re.kr</email></aff><author-notes><corresp id="c1-cells-08-00296"><label>*</label>Correspondence: <email>hjyou@ncc.re.kr</email>; Tel.: +82-31-920-2206</corresp></author-notes><pub-date pub-type="epub"><day>30</day><month>3</month><year>2019</year></pub-date><pub-date pub-type="collection"><month>4</month><year>2019</year></pub-date><volume>8</volume><issue>4</issue><elocation-id>296</elocation-id><history><date date-type="received"><day>06</day><month>3</month><year>2019</year></date><date date-type="accepted"><day>29</day><month>3</month><year>2019</year></date></history><permissions><copyright-statement>© 2019 by the authors.</copyright-statement><copyright-year>2019</copyright-year><license license-type="open-access"><license-p>Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>).</license-p></license></permissions><abstract><p>Autophagy is a cellular process that disrupts and uses unnecessary or malfunctioning components for cellular homeostasis. Evidence has shown a role for autophagy in tumor cell survival, but the molecular determinants that define sensitivity against autophagic regulation in cancers are not clear. Importantly, we found that breast cancer cells with low expression levels of a zinc-finger protein, ZNF143 (MCF7 sh-ZNF143), showed better survival than control cells (MCF7 sh-Control) under starvation, which was compromised with chloroquine, an autophagy inhibitor. In addition, there were more autophagic vesicles in MCF7 sh-ZNF143 cells than in MCF7 sh-Control cells, and proteins related with the autophagic process, such as Beclin1, p62, and ATGs, were altered in cells with less ZNF143. ZNF143 knockdown affected the stability of p53, which showed a dependence on MG132, a proteasome inhibitor. Data from proteome profiling in breast cancer cells with less ZNF143 suggest a role of NAD(P)H quinone dehydrogenase 1(NQO1) for p53 stability. Taken together, we showed that a subset of breast cancer cells with low expression of ZNF143 might exhibit better survival via an autophagic process by regulating the p53–Beclin1 axis, corroborating the necessity of blocking autophagy for the best therapy.</p></abstract><kwd-group><kwd>ZNF143</kwd><kwd>p53</kwd><kwd>NQO1</kwd><kwd>autophagy</kwd><kwd>metabolic stress</kwd><kwd>survival</kwd></kwd-group></article-meta></front><floats-group><fig id="cells-08-00296-f001" orientation="portrait" position="float"><label>Figure 1</label><caption><p>Breast cancer cells with decreased ZNF143 show better survival in glucose- and/or FBS-deprived conditions, which are chloroquine-dependent. (<bold>A</bold>,<bold>B</bold>) MCF7 sh-Control and sh-ZNF143 cells were grown in four different conditions for 24 h, and viable cells were counted by fluorescence-activated cell sorting. G and F denote glucose and FBS, respectively. (<bold>C</bold>–<bold>E</bold>) Cells were plated on 96-well plates and grown for 24 h. The cells were then maintained in four different conditions in terms of FBS and glucose, and cell survival or growth was monitored by capturing images every 2 h over 4 days. Cells were maintained in the presence of 10 μM chloroquine (<bold>D</bold>), 100 nM Wortmannin (<bold>E</bold>), or dimethysulfoxide (vehicle). Relative confluency is shown in the graphs. Data are expressed as means ± S.E. of at least three independent experiments. Statistical significance was assessed using paired Student’s <italic>t</italic>-tests (* <italic>p</italic> < 0.05 and ** <italic>p</italic> < 0.005). Results shown are representative of at least three independent experiments.</p></caption><graphic xlink:href="cells-08-00296-g001"></graphic></fig><fig id="cells-08-00296-f002" orientation="portrait" position="float"><label>Figure 2</label><caption><p>More autophagic vesicles are observed in ZNF143 knockdown cells than in control cells. (<bold>A</bold>) Growing cells were maintained in growing media or fetal bovine serum-free media for 24 h and then fixed for TEM. (<bold>B</bold>,<bold>C</bold>) cells were grown on coverslips for 24 h and then exposed to four different media for an additional 24 h to monitor autophagic processes by autophagosome-selective marker labeling in live cells. Foci were visualized by confocal microscopy, quantified by using ImageJ software, and statistically analyzed by GraphPad software (<bold>C</bold>). Results shown are representative of at least three independent experiments.</p></caption><graphic xlink:href="cells-08-00296-g002"></graphic></fig><fig id="cells-08-00296-f003" orientation="portrait" position="float"><label>Figure 3</label><caption><p>Proteins related to autophagic processes are altered in MCF7 sh-ZNF143 cells. (<bold>A</bold>) Growing cells were harvested for immunoblotting for autophagic-related proteins. (<bold>B</bold>) Growing cells were exposed to four different media (G+/F+, G+/F−, G−/F−, G−/F+; G: glucose, F: FBS, respectively) for additional time periods, as indicated, then harvested for immunoblotting. Results shown are representative of at least three independent experiments.</p></caption><graphic xlink:href="cells-08-00296-g003"></graphic></fig><fig id="cells-08-00296-f004" orientation="portrait" position="float"><label>Figure 4</label><caption><p>The p53 protein is altered in MCF7 sh-ZNF143 cells in a proteasome-dependent manner. (<bold>A</bold>) Growing or FBS-starved cells were harvested and subjected to immunoblotting. (<bold>B</bold>) Growing cells were harvested for RT-PCR. (<bold>C</bold>) Growing cells were transfected with pFLAG-CMV-hZNF143 or empty vector for 24 h and harvested for immunoblotting. (<bold>D</bold>) Growing cells were harvested for immunoblotting. Cells were treated with MG132 (20 μM, 6 h), chloroquine (50 μM, 18 h), or vehicle. The results shown are representative of at least three independent experiments.</p></caption><graphic xlink:href="cells-08-00296-g004"></graphic></fig><fig id="cells-08-00296-f005" orientation="portrait" position="float"><label>Figure 5</label><caption><p>NQO1 is reduced in ZNF143-silenced breast cancer cells, and is important for p53 stability. (<bold>A</bold>) Growing cells were harvested and subjected to liquid chromatography–mass spectrometry to profile altered proteins by ZNF143 knockdown. Approximately 5000 proteins were profiled, and 177 proteins were significantly altered for pathway analysis. (<bold>B</bold>) Growing cells were harvested for immunoblotting to determine the expression of NQO1. (<bold>C</bold>) Growing cells were transfected with a vector (pFLAG-CMV) or a plasmid encoding the full length ZNF143 (hZNF143FL) for 24 h and harvested for immunoblotting. (<bold>D</bold>) Growing cells were harvested for ROS measurements by flow cytometry. Cells were incubated with 10 μM H<sub>2</sub>DCFDA for 10 min before harvesting. (<bold>E</bold>) Growing cells were harvested for RT-PCR to determine the expression of NQO1, PTGR1, and KYNU at the mRNA level. Results shown are representative of at least three independent experiments.</p></caption><graphic xlink:href="cells-08-00296-g005"></graphic></fig><fig id="cells-08-00296-f006" orientation="portrait" position="float"><label>Figure 6</label><caption><p>ZNF143 expression is related to disease-free survival of breast cancer patients according to TCGA. (<bold>A</bold>) Higher levels of ZNF143 mRNA expression and copy number alterations were associated with increased disease-free survival in the TCGA cohort. The log-rank value was 0.038. Patients with higher levels of ZNF143 gene expression are shown in red and patients without higher levels of ZNF143 gene expression are shown in blue. (<bold>B</bold>) Lower levels of ZNF143 mRNA expression were associated with decreased disease-free survival in the TCGA cohort. The log-rank value was 0.030. Patients with lower levels of ZNF143 gene expression are shown in red and patients without lower levels of ZNF143 gene expression are shown in blue. In all analyses, patients not applicable for any of the selected attribute(s) were excluded.</p></caption><graphic xlink:href="cells-08-00296-g006"></graphic></fig><table-wrap id="cells-08-00296-t001" orientation="portrait" position="float"><object-id pub-id-type="pii">cells-08-00296-t001_Table 1</object-id><label>Table 1</label><caption><p>Gene Co-occurrent Alteration.</p></caption><table frame="hsides" rules="groups"><thead><tr><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Gene A</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Gene B</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Neither</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">A Not B</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">B Not A</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Both</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Log Odds Ratio</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1"><italic>p</italic>-Value</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Adjusted <italic>p</italic>-Value</th><th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Tendency</th></tr></thead><tbody><tr><td align="center" valign="middle" rowspan="1" colspan="1"><italic>NQO1</italic></td><td align="center" valign="middle" rowspan="1" colspan="1"><italic>ZNF143</italic></td><td align="center" valign="middle" rowspan="1" colspan="1">1019</td><td align="center" valign="middle" rowspan="1" colspan="1">40</td><td align="center" valign="middle" rowspan="1" colspan="1">39</td><td align="center" valign="middle" rowspan="1" colspan="1">7</td><td align="center" valign="middle" rowspan="1" colspan="1">1.52</td><td align="center" valign="middle" rowspan="1" colspan="1">0.002</td><td align="center" valign="middle" rowspan="1" colspan="1">0.007</td><td align="center" valign="middle" rowspan="1" colspan="1">Co-occurrence *</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1"><italic>ZNF143</italic></td><td align="center" valign="middle" rowspan="1" colspan="1"><italic>TP53</italic></td><td align="center" valign="middle" rowspan="1" colspan="1">717</td><td align="center" valign="middle" rowspan="1" colspan="1">22</td><td align="center" valign="middle" rowspan="1" colspan="1">342</td><td align="center" valign="middle" rowspan="1" colspan="1">24</td><td align="center" valign="middle" rowspan="1" colspan="1">0.827</td><td align="center" valign="middle" rowspan="1" colspan="1">0.005</td><td align="center" valign="middle" rowspan="1" colspan="1">0.015</td><td align="center" valign="middle" rowspan="1" colspan="1">Co-occurrence *</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><italic>NQO1</italic></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><italic>TP53</italic></td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">710</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">29</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">348</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">18</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.236</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.267</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.801</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Co-occurrence</td></tr></tbody></table><table-wrap-foot><fn><p>* adjusted <italic>p</italic>-Value < 0.05, significant.</p></fn></table-wrap-foot></table-wrap></floats-group></pmc><affiliations><list><country><li>Corée du Sud</li></country></list><tree><noCountry><name sortKey="Choi, Hyosun" sort="Choi, Hyosun" uniqKey="Choi H" first="Hyosun" last="Choi">Hyosun Choi</name><name sortKey="Hong, Dong Wan" sort="Hong, Dong Wan" uniqKey="Hong D" first="Dong Wan" last="Hong">Dong Wan Hong</name><name sortKey="Jo, Mun Jeong" sort="Jo, Mun Jeong" uniqKey="Jo M" first="Mun Jeong" last="Jo">Mun Jeong Jo</name><name sortKey="Kim, Kyung Hee" sort="Kim, Kyung Hee" uniqKey="Kim K" first="Kyung-Hee" last="Kim">Kyung-Hee Kim</name><name sortKey="Lee, Yun Jeong" sort="Lee, Yun Jeong" uniqKey="Lee Y" first="Yun Jeong" last="Lee">Yun Jeong Lee</name><name sortKey="Mun, Ji Young" sort="Mun, Ji Young" uniqKey="Mun J" first="Ji Young" last="Mun">Ji Young Mun</name><name sortKey="Myung, Jae Kyung" sort="Myung, Jae Kyung" uniqKey="Myung J" first="Jae Kyung" last="Myung">Jae Kyung Myung</name><name sortKey="Paek, A Rome" sort="Paek, A Rome" uniqKey="Paek A" first="A Rome" last="Paek">A Rome Paek</name><name sortKey="Park, Jongkeun" sort="Park, Jongkeun" uniqKey="Park J" first="Jongkeun" last="Park">Jongkeun Park</name><name sortKey="You, Hye Jin" sort="You, Hye Jin" uniqKey="You H" first="Hye Jin" last="You">Hye Jin You</name></noCountry><country name="Corée du Sud"><noRegion><name sortKey="Cheong, Heesun" sort="Cheong, Heesun" uniqKey="Cheong H" first="Heesun" last="Cheong">Heesun Cheong</name></noRegion></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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