AKT-mediated phosphorylation enhances protein stability and transcription activity of ZNF322A to promote lung cancer progression
ZNF322A is an oncogenic zinc-finger transcription factor. Our published results show that ZNF322A positively regulates transcription of alpha-adducin (ADD1) and cyclin D1 (CCND1) to promote tumorgenicity of lung cancer. However, the upstream regulatory mechanisms of ZNF322A protein function remain e...
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| Veröffentlicht in: | Oncogene 2019-10, Vol.38 (41), p.6723-6736 |
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| creator | Liao, Sheng-You Kuo, I-Ying Chen, Yu-Ting Liao, Pao-Chi Liu, Ya-Fen Wu, Hsin-Yi Lai, Wu-Wei Wang, Yi-Ching |
| description | ZNF322A is an oncogenic zinc-finger transcription factor. Our published results show that ZNF322A positively regulates transcription of
alpha-adducin (ADD1)
and
cyclin D1 (CCND1)
to promote tumorgenicity of lung cancer. However, the upstream regulatory mechanisms of ZNF322A protein function remain elusive. Here, we demonstrate that AKT could phosphorylate ZNF322A by in vitro kinase assay and cell-based mass spectrometry analysis. Overexpression of AKT promoted ZNF322A protein stability and transcriptional activity, whereas these effects were inhibited by knockdown of AKT or treating with AKT inhibitor. We studied AKT-mediated phosphorylation sites, viz. Thr-150, Ser-224, Thr-234, and Thr-262. ZNF322A phosphorylation at Thr-262 by AKT promoted ZNF322A protein stability thus increased
ADD1
promoter activity. Interestingly, phosphorylation at Thr-150, Ser-224, and Thr-234 enhanced transcription activity without affecting protein stability of ZNF322A. Chromatin immunoprecipitation and DNA affinity precipitation assays showed that ZNF322A phosphorylation defective mutants Thr-150A, Ser-224A, and Thr-234A attenuated chromatin binding and DNA binding affinity to
ADD1
and
CCND1
promoters compared with wild-type ZNF322A. Furthermore, AKT-mediated Thr-150, Ser-224, Thr-234, and Thr-262 phosphorylation promoted lung cancer cell growth and metastasis in vitro and in vivo. Clinically, expression of phosphorylated ZNF322A (p-ZNF) correlated with actively phosphorylated AKT (p-AKT) in tumor specimens from 150 lung cancer patients. Multivariate Cox regression analysis indicated that combined p-AKT and p-ZNF expression profile was an independent factor to predict the clinical outcome in lung cancer patients. Our results reveal a new mechanism of AKT signaling in promoting ZNF322A protein stability and transcriptional activity in lung cancer cell, xenograft, and clinical models. |
| doi_str_mv | 10.1038/s41388-019-0928-x |
| format | Article |
| fullrecord | <record><control><sourceid>gale_proqu</sourceid><recordid>TN_cdi_proquest_journals_2303167223</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><galeid>A602270142</galeid><sourcerecordid>A602270142</sourcerecordid><originalsourceid>FETCH-LOGICAL-c439t-31d7083b2b601db946cdd1ce453247540b3991d64bb4097edb0d94a149bfe98f3</originalsourceid><addsrcrecordid>eNp1kU1rVDEUhoNY7Fj9AW4k4Dr15ON-ZDkU24rFburGTcjXnabcmzsmGens_OnN7VSLoIQQOOd93pPDi9A7CqcUeP8xC8r7ngCVBCTryf0LtKKia0nTSPESrUA2QCTj7Bi9zvkOADoJ7BU65pRL2YpuhX6tv9yQybugi3d4ezvnetN-1CXMEft4q6P1GW_TXHyIOBdtwhjKHuvocEk6ZpvC9lGsbQk_l9Y84O9fzzlja1zmBZ0qjMdd3GC72KWltkk-54q9QUeDHrN_-_SeoG_nn27OLsnV9cXns_UVsYLLQjh1HfTcMNMCdUaK1jpHrRcNZ6JrBJi6EXWtMEaA7Lwz4KTQVEgzeNkP_AR9OPjW2T92Phd1N-9SrCMV48Bp2zHGn1UbPXoV4jDXHe0UslXrFhjrgApWVaf_UNXj_BTsHP0Qav0vgB4Am-ackx_UNoVJp72ioJYo1SFKVaNUS5TqvjLvnz68MzWgP8Tv7KqAHQS5tuLGp-eN_u_6AINqqi0</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2303167223</pqid></control><display><type>article</type><title>AKT-mediated phosphorylation enhances protein stability and transcription activity of ZNF322A to promote lung cancer progression</title><source>MEDLINE</source><source>Springer Nature - Complete Springer Journals</source><creator>Liao, Sheng-You ; Kuo, I-Ying ; Chen, Yu-Ting ; Liao, Pao-Chi ; Liu, Ya-Fen ; Wu, Hsin-Yi ; Lai, Wu-Wei ; Wang, Yi-Ching</creator><creatorcontrib>Liao, Sheng-You ; Kuo, I-Ying ; Chen, Yu-Ting ; Liao, Pao-Chi ; Liu, Ya-Fen ; Wu, Hsin-Yi ; Lai, Wu-Wei ; Wang, Yi-Ching</creatorcontrib><description>ZNF322A is an oncogenic zinc-finger transcription factor. Our published results show that ZNF322A positively regulates transcription of
alpha-adducin (ADD1)
and
cyclin D1 (CCND1)
to promote tumorgenicity of lung cancer. However, the upstream regulatory mechanisms of ZNF322A protein function remain elusive. Here, we demonstrate that AKT could phosphorylate ZNF322A by in vitro kinase assay and cell-based mass spectrometry analysis. Overexpression of AKT promoted ZNF322A protein stability and transcriptional activity, whereas these effects were inhibited by knockdown of AKT or treating with AKT inhibitor. We studied AKT-mediated phosphorylation sites, viz. Thr-150, Ser-224, Thr-234, and Thr-262. ZNF322A phosphorylation at Thr-262 by AKT promoted ZNF322A protein stability thus increased
ADD1
promoter activity. Interestingly, phosphorylation at Thr-150, Ser-224, and Thr-234 enhanced transcription activity without affecting protein stability of ZNF322A. Chromatin immunoprecipitation and DNA affinity precipitation assays showed that ZNF322A phosphorylation defective mutants Thr-150A, Ser-224A, and Thr-234A attenuated chromatin binding and DNA binding affinity to
ADD1
and
CCND1
promoters compared with wild-type ZNF322A. Furthermore, AKT-mediated Thr-150, Ser-224, Thr-234, and Thr-262 phosphorylation promoted lung cancer cell growth and metastasis in vitro and in vivo. Clinically, expression of phosphorylated ZNF322A (p-ZNF) correlated with actively phosphorylated AKT (p-AKT) in tumor specimens from 150 lung cancer patients. Multivariate Cox regression analysis indicated that combined p-AKT and p-ZNF expression profile was an independent factor to predict the clinical outcome in lung cancer patients. Our results reveal a new mechanism of AKT signaling in promoting ZNF322A protein stability and transcriptional activity in lung cancer cell, xenograft, and clinical models.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/s41388-019-0928-x</identifier><identifier>PMID: 31399647</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>101/58 ; 13/51 ; 13/95 ; 631/337/458/1733 ; 631/337/572 ; 631/67/1612/1350 ; 631/67/1857 ; 631/67/395 ; 64/60 ; 82/1 ; 82/29 ; 82/80 ; 96/106 ; Adducin ; Affinity ; AKT protein ; Apoptosis ; Cell Biology ; Cell culture ; Cell Line, Tumor ; Cell Proliferation ; Cellular signal transduction ; Chromatin ; Cyclin D1 ; Deoxyribonucleic acid ; Development and progression ; DNA ; Epidermal Growth Factor - metabolism ; Genetic aspects ; Genetic transcription ; Human Genetics ; Humans ; Immunoprecipitation ; Internal Medicine ; Kinases ; Lung cancer ; Lung Neoplasms - metabolism ; Lung Neoplasms - pathology ; Mass spectroscopy ; Medicine ; Medicine & Public Health ; Metastases ; Neoplasm Metastasis ; Oncogene Proteins - metabolism ; Oncology ; Patients ; Phosphorylation ; Prognosis ; Promoter Regions, Genetic ; Protein Stability ; Proteins ; Proto-Oncogene Proteins c-akt - metabolism ; Signal Transduction ; Transcription Factors - metabolism ; Transcription, Genetic ; Xenografts ; Zinc finger proteins</subject><ispartof>Oncogene, 2019-10, Vol.38 (41), p.6723-6736</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited 2019</rights><rights>COPYRIGHT 2019 Nature Publishing Group</rights><rights>Copyright Nature Publishing Group Oct 2019</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c439t-31d7083b2b601db946cdd1ce453247540b3991d64bb4097edb0d94a149bfe98f3</citedby><cites>FETCH-LOGICAL-c439t-31d7083b2b601db946cdd1ce453247540b3991d64bb4097edb0d94a149bfe98f3</cites><orcidid>0000-0002-7694-2067</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://link.springer.com/content/pdf/10.1038/s41388-019-0928-x$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41388-019-0928-x$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27903,27904,41467,42536,51297</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31399647$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liao, Sheng-You</creatorcontrib><creatorcontrib>Kuo, I-Ying</creatorcontrib><creatorcontrib>Chen, Yu-Ting</creatorcontrib><creatorcontrib>Liao, Pao-Chi</creatorcontrib><creatorcontrib>Liu, Ya-Fen</creatorcontrib><creatorcontrib>Wu, Hsin-Yi</creatorcontrib><creatorcontrib>Lai, Wu-Wei</creatorcontrib><creatorcontrib>Wang, Yi-Ching</creatorcontrib><title>AKT-mediated phosphorylation enhances protein stability and transcription activity of ZNF322A to promote lung cancer progression</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>ZNF322A is an oncogenic zinc-finger transcription factor. Our published results show that ZNF322A positively regulates transcription of
alpha-adducin (ADD1)
and
cyclin D1 (CCND1)
to promote tumorgenicity of lung cancer. However, the upstream regulatory mechanisms of ZNF322A protein function remain elusive. Here, we demonstrate that AKT could phosphorylate ZNF322A by in vitro kinase assay and cell-based mass spectrometry analysis. Overexpression of AKT promoted ZNF322A protein stability and transcriptional activity, whereas these effects were inhibited by knockdown of AKT or treating with AKT inhibitor. We studied AKT-mediated phosphorylation sites, viz. Thr-150, Ser-224, Thr-234, and Thr-262. ZNF322A phosphorylation at Thr-262 by AKT promoted ZNF322A protein stability thus increased
ADD1
promoter activity. Interestingly, phosphorylation at Thr-150, Ser-224, and Thr-234 enhanced transcription activity without affecting protein stability of ZNF322A. Chromatin immunoprecipitation and DNA affinity precipitation assays showed that ZNF322A phosphorylation defective mutants Thr-150A, Ser-224A, and Thr-234A attenuated chromatin binding and DNA binding affinity to
ADD1
and
CCND1
promoters compared with wild-type ZNF322A. Furthermore, AKT-mediated Thr-150, Ser-224, Thr-234, and Thr-262 phosphorylation promoted lung cancer cell growth and metastasis in vitro and in vivo. Clinically, expression of phosphorylated ZNF322A (p-ZNF) correlated with actively phosphorylated AKT (p-AKT) in tumor specimens from 150 lung cancer patients. Multivariate Cox regression analysis indicated that combined p-AKT and p-ZNF expression profile was an independent factor to predict the clinical outcome in lung cancer patients. Our results reveal a new mechanism of AKT signaling in promoting ZNF322A protein stability and transcriptional activity in lung cancer cell, xenograft, and clinical models.</description><subject>101/58</subject><subject>13/51</subject><subject>13/95</subject><subject>631/337/458/1733</subject><subject>631/337/572</subject><subject>631/67/1612/1350</subject><subject>631/67/1857</subject><subject>631/67/395</subject><subject>64/60</subject><subject>82/1</subject><subject>82/29</subject><subject>82/80</subject><subject>96/106</subject><subject>Adducin</subject><subject>Affinity</subject><subject>AKT protein</subject><subject>Apoptosis</subject><subject>Cell Biology</subject><subject>Cell culture</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation</subject><subject>Cellular signal transduction</subject><subject>Chromatin</subject><subject>Cyclin D1</subject><subject>Deoxyribonucleic acid</subject><subject>Development and progression</subject><subject>DNA</subject><subject>Epidermal Growth Factor - metabolism</subject><subject>Genetic aspects</subject><subject>Genetic transcription</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Immunoprecipitation</subject><subject>Internal Medicine</subject><subject>Kinases</subject><subject>Lung cancer</subject><subject>Lung Neoplasms - metabolism</subject><subject>Lung Neoplasms - pathology</subject><subject>Mass spectroscopy</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Metastases</subject><subject>Neoplasm Metastasis</subject><subject>Oncogene Proteins - metabolism</subject><subject>Oncology</subject><subject>Patients</subject><subject>Phosphorylation</subject><subject>Prognosis</subject><subject>Promoter Regions, Genetic</subject><subject>Protein Stability</subject><subject>Proteins</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Signal Transduction</subject><subject>Transcription Factors - metabolism</subject><subject>Transcription, Genetic</subject><subject>Xenografts</subject><subject>Zinc finger proteins</subject><issn>0950-9232</issn><issn>1476-5594</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>BENPR</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp1kU1rVDEUhoNY7Fj9AW4k4Dr15ON-ZDkU24rFburGTcjXnabcmzsmGens_OnN7VSLoIQQOOd93pPDi9A7CqcUeP8xC8r7ngCVBCTryf0LtKKia0nTSPESrUA2QCTj7Bi9zvkOADoJ7BU65pRL2YpuhX6tv9yQybugi3d4ezvnetN-1CXMEft4q6P1GW_TXHyIOBdtwhjKHuvocEk6ZpvC9lGsbQk_l9Y84O9fzzlja1zmBZ0qjMdd3GC72KWltkk-54q9QUeDHrN_-_SeoG_nn27OLsnV9cXns_UVsYLLQjh1HfTcMNMCdUaK1jpHrRcNZ6JrBJi6EXWtMEaA7Lwz4KTQVEgzeNkP_AR9OPjW2T92Phd1N-9SrCMV48Bp2zHGn1UbPXoV4jDXHe0UslXrFhjrgApWVaf_UNXj_BTsHP0Qav0vgB4Am-ackx_UNoVJp72ioJYo1SFKVaNUS5TqvjLvnz68MzWgP8Tv7KqAHQS5tuLGp-eN_u_6AINqqi0</recordid><startdate>20191010</startdate><enddate>20191010</enddate><creator>Liao, Sheng-You</creator><creator>Kuo, I-Ying</creator><creator>Chen, Yu-Ting</creator><creator>Liao, Pao-Chi</creator><creator>Liu, Ya-Fen</creator><creator>Wu, Hsin-Yi</creator><creator>Lai, Wu-Wei</creator><creator>Wang, Yi-Ching</creator><general>Nature Publishing Group UK</general><general>Nature Publishing Group</general><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>Q9U</scope><scope>RC3</scope><orcidid>https://orcid.org/0000-0002-7694-2067</orcidid></search><sort><creationdate>20191010</creationdate><title>AKT-mediated phosphorylation enhances protein stability and transcription activity of ZNF322A to promote lung cancer progression</title><author>Liao, Sheng-You ; Kuo, I-Ying ; Chen, Yu-Ting ; Liao, Pao-Chi ; Liu, Ya-Fen ; Wu, Hsin-Yi ; Lai, Wu-Wei ; Wang, Yi-Ching</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c439t-31d7083b2b601db946cdd1ce453247540b3991d64bb4097edb0d94a149bfe98f3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>101/58</topic><topic>13/51</topic><topic>13/95</topic><topic>631/337/458/1733</topic><topic>631/337/572</topic><topic>631/67/1612/1350</topic><topic>631/67/1857</topic><topic>631/67/395</topic><topic>64/60</topic><topic>82/1</topic><topic>82/29</topic><topic>82/80</topic><topic>96/106</topic><topic>Adducin</topic><topic>Affinity</topic><topic>AKT protein</topic><topic>Apoptosis</topic><topic>Cell Biology</topic><topic>Cell culture</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation</topic><topic>Cellular signal transduction</topic><topic>Chromatin</topic><topic>Cyclin D1</topic><topic>Deoxyribonucleic acid</topic><topic>Development and progression</topic><topic>DNA</topic><topic>Epidermal Growth Factor - metabolism</topic><topic>Genetic aspects</topic><topic>Genetic transcription</topic><topic>Human Genetics</topic><topic>Humans</topic><topic>Immunoprecipitation</topic><topic>Internal Medicine</topic><topic>Kinases</topic><topic>Lung cancer</topic><topic>Lung Neoplasms - metabolism</topic><topic>Lung Neoplasms - pathology</topic><topic>Mass spectroscopy</topic><topic>Medicine</topic><topic>Medicine & Public Health</topic><topic>Metastases</topic><topic>Neoplasm Metastasis</topic><topic>Oncogene Proteins - metabolism</topic><topic>Oncology</topic><topic>Patients</topic><topic>Phosphorylation</topic><topic>Prognosis</topic><topic>Promoter Regions, Genetic</topic><topic>Protein Stability</topic><topic>Proteins</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Signal Transduction</topic><topic>Transcription Factors - metabolism</topic><topic>Transcription, Genetic</topic><topic>Xenografts</topic><topic>Zinc finger proteins</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liao, Sheng-You</creatorcontrib><creatorcontrib>Kuo, I-Ying</creatorcontrib><creatorcontrib>Chen, Yu-Ting</creatorcontrib><creatorcontrib>Liao, Pao-Chi</creatorcontrib><creatorcontrib>Liu, Ya-Fen</creatorcontrib><creatorcontrib>Wu, Hsin-Yi</creatorcontrib><creatorcontrib>Lai, Wu-Wei</creatorcontrib><creatorcontrib>Wang, Yi-Ching</creatorcontrib><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 Basic</collection><collection>Genetics Abstracts</collection><jtitle>Oncogene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liao, Sheng-You</au><au>Kuo, I-Ying</au><au>Chen, Yu-Ting</au><au>Liao, Pao-Chi</au><au>Liu, Ya-Fen</au><au>Wu, Hsin-Yi</au><au>Lai, Wu-Wei</au><au>Wang, Yi-Ching</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>AKT-mediated phosphorylation enhances protein stability and transcription activity of ZNF322A to promote lung cancer progression</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><addtitle>Oncogene</addtitle><date>2019-10-10</date><risdate>2019</risdate><volume>38</volume><issue>41</issue><spage>6723</spage><epage>6736</epage><pages>6723-6736</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><abstract>ZNF322A is an oncogenic zinc-finger transcription factor. Our published results show that ZNF322A positively regulates transcription of
alpha-adducin (ADD1)
and
cyclin D1 (CCND1)
to promote tumorgenicity of lung cancer. However, the upstream regulatory mechanisms of ZNF322A protein function remain elusive. Here, we demonstrate that AKT could phosphorylate ZNF322A by in vitro kinase assay and cell-based mass spectrometry analysis. Overexpression of AKT promoted ZNF322A protein stability and transcriptional activity, whereas these effects were inhibited by knockdown of AKT or treating with AKT inhibitor. We studied AKT-mediated phosphorylation sites, viz. Thr-150, Ser-224, Thr-234, and Thr-262. ZNF322A phosphorylation at Thr-262 by AKT promoted ZNF322A protein stability thus increased
ADD1
promoter activity. Interestingly, phosphorylation at Thr-150, Ser-224, and Thr-234 enhanced transcription activity without affecting protein stability of ZNF322A. Chromatin immunoprecipitation and DNA affinity precipitation assays showed that ZNF322A phosphorylation defective mutants Thr-150A, Ser-224A, and Thr-234A attenuated chromatin binding and DNA binding affinity to
ADD1
and
CCND1
promoters compared with wild-type ZNF322A. Furthermore, AKT-mediated Thr-150, Ser-224, Thr-234, and Thr-262 phosphorylation promoted lung cancer cell growth and metastasis in vitro and in vivo. Clinically, expression of phosphorylated ZNF322A (p-ZNF) correlated with actively phosphorylated AKT (p-AKT) in tumor specimens from 150 lung cancer patients. Multivariate Cox regression analysis indicated that combined p-AKT and p-ZNF expression profile was an independent factor to predict the clinical outcome in lung cancer patients. Our results reveal a new mechanism of AKT signaling in promoting ZNF322A protein stability and transcriptional activity in lung cancer cell, xenograft, and clinical models.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>31399647</pmid><doi>10.1038/s41388-019-0928-x</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0002-7694-2067</orcidid></addata></record> |
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| ispartof | Oncogene, 2019-10, Vol.38 (41), p.6723-6736 |
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| subjects | 101/58 13/51 13/95 631/337/458/1733 631/337/572 631/67/1612/1350 631/67/1857 631/67/395 64/60 82/1 82/29 82/80 96/106 Adducin Affinity AKT protein Apoptosis Cell Biology Cell culture Cell Line, Tumor Cell Proliferation Cellular signal transduction Chromatin Cyclin D1 Deoxyribonucleic acid Development and progression DNA Epidermal Growth Factor - metabolism Genetic aspects Genetic transcription Human Genetics Humans Immunoprecipitation Internal Medicine Kinases Lung cancer Lung Neoplasms - metabolism Lung Neoplasms - pathology Mass spectroscopy Medicine Medicine & Public Health Metastases Neoplasm Metastasis Oncogene Proteins - metabolism Oncology Patients Phosphorylation Prognosis Promoter Regions, Genetic Protein Stability Proteins Proto-Oncogene Proteins c-akt - metabolism Signal Transduction Transcription Factors - metabolism Transcription, Genetic Xenografts Zinc finger proteins |
| title | AKT-mediated phosphorylation enhances protein stability and transcription activity of ZNF322A to promote lung cancer progression |
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