HA117 endows HL60 cells with a stem-like signature by inhibiting the degradation of DNMT1 via its ability to down-regulate expression of the GGL domain of RGS6
All-trans retinoic acid (ATRA) induces complete remission in almost all patients with acute promyelocytic leukemia (APL) via its ability to induce the in vivo differentiation of APL blasts. However, prolonged ATRA treatment can result in drug resistance. In previous studies, we generated a multi-dru...
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| Veröffentlicht in: | PloS one 2017-06, Vol.12 (6), p.e0180142-e0180142 |
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| creator | Li, Shuangshuang Jin, Xianqing Wu, Huan Wang, Yi Li, Xiaoqing Guo, Yuxia Liang, Shaoyan |
| description | All-trans retinoic acid (ATRA) induces complete remission in almost all patients with acute promyelocytic leukemia (APL) via its ability to induce the in vivo differentiation of APL blasts. However, prolonged ATRA treatment can result in drug resistance. In previous studies, we generated a multi-drug-resistant HL60/ATRA cell line and found it to contain a new drug resistance-related gene segment, HA117. In this study, we demonstrate that ATRA induces multi-drug-resistant subpopulations of HL60 cells with a putative stem-like signature by up-regulating the expression of the new gene segment HA117. Western blot analysis and quantitative real-time PCR demonstrated that HA117 causes alternative splicing of regulator of G-protein signaling 6 (RGS6) and down-regulation of the expression of the GGL domain of RGS6, which plays an important role in DNA methyltransferase 1 (DNMT1) degradation. Moreover, DNMT1 expression was increased in multi-drug resistance HL60/ATRA cells. Knockdown of HA117 restored expression of the GGL domain and blocked DNMT1 expression. Moreover, resistant cells displayed a putative stem-like signature with increased expression of cancer steam cell markers CD133 and CD123. The stem cell marker, Nanog, was significantly up-regulated. In conclusion, our study shows that HA117 potentially promotes the stem-like signature of the HL60/ATRA cell line by inhibiting by the ubiquitination and degradation of DNMT1 and by down-regulating the expression of the GGL domain of RGS6. These results throw light on the cellular events associated with the ATRA-induced multi-drug resistance phenotype in acute leukemia. |
| doi_str_mv | 10.1371/journal.pone.0180142 |
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However, prolonged ATRA treatment can result in drug resistance. In previous studies, we generated a multi-drug-resistant HL60/ATRA cell line and found it to contain a new drug resistance-related gene segment, HA117. In this study, we demonstrate that ATRA induces multi-drug-resistant subpopulations of HL60 cells with a putative stem-like signature by up-regulating the expression of the new gene segment HA117. Western blot analysis and quantitative real-time PCR demonstrated that HA117 causes alternative splicing of regulator of G-protein signaling 6 (RGS6) and down-regulation of the expression of the GGL domain of RGS6, which plays an important role in DNA methyltransferase 1 (DNMT1) degradation. Moreover, DNMT1 expression was increased in multi-drug resistance HL60/ATRA cells. Knockdown of HA117 restored expression of the GGL domain and blocked DNMT1 expression. Moreover, resistant cells displayed a putative stem-like signature with increased expression of cancer steam cell markers CD133 and CD123. The stem cell marker, Nanog, was significantly up-regulated. In conclusion, our study shows that HA117 potentially promotes the stem-like signature of the HL60/ATRA cell line by inhibiting by the ubiquitination and degradation of DNMT1 and by down-regulating the expression of the GGL domain of RGS6. These results throw light on the cellular events associated with the ATRA-induced multi-drug resistance phenotype in acute leukemia.</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0180142</identifier><identifier>PMID: 28665981</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Acute myelocytic leukemia ; Acute promyeloid leukemia ; Alternative splicing ; APL (programming language) ; Binding sites ; Biology and life sciences ; Brain cancer ; Cancer ; Cancer therapies ; CD123 antigen ; Cell cycle ; Child development ; Children & youth ; Cooperation ; Degradation ; Deoxyribonucleic acid ; Differentiation ; DNA ; DNA methylation ; DNA methyltransferase ; DNMT1 protein ; Down-Regulation ; Drug resistance ; Drug Resistance, Neoplasm ; Drug therapy ; Education ; Epigenetics ; Gastrointestinal surgery ; Gene expression ; Genes ; Genetic aspects ; HL-60 Cells ; Humans ; Laboratories ; Leukemia ; Leukemia, Promyelocytic, Acute - drug therapy ; Leukemia, Promyelocytic, Acute - pathology ; Markers ; Medicine and Health Sciences ; Multidrug resistance ; Neoplasm Proteins - physiology ; Neoplastic Stem Cells - metabolism ; Neoplastic Stem Cells - pathology ; Patients ; Pediatrics ; Physiological aspects ; Polymerase chain reaction ; Promyeloid leukemia ; Proteins ; Proteolysis ; Real time ; Remission ; Repressor Proteins - metabolism ; Research and analysis methods ; Retinoic acid ; RGS Proteins - chemistry ; RGS Proteins - metabolism ; Science ; Steam ; Stem cells ; Subpopulations ; Tretinoin ; Tretinoin - pharmacology ; Tretinoin - therapeutic use ; Tumors ; Ubiquitination</subject><ispartof>PloS one, 2017-06, Vol.12 (6), p.e0180142-e0180142</ispartof><rights>COPYRIGHT 2017 Public Library of Science</rights><rights>2017 Li et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2017 Li et al 2017 Li et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c692t-7f227ef777d556bb7783025e8052846fef0e5411bba33d314325dd7779cd8bb73</citedby><cites>FETCH-LOGICAL-c692t-7f227ef777d556bb7783025e8052846fef0e5411bba33d314325dd7779cd8bb73</cites><orcidid>0000-0002-6433-8719</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5493346/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5493346/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,864,885,2102,2928,23866,27924,27925,53791,53793,79600,79601</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28665981$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Ahmad, Aamir</contributor><creatorcontrib>Li, Shuangshuang</creatorcontrib><creatorcontrib>Jin, Xianqing</creatorcontrib><creatorcontrib>Wu, Huan</creatorcontrib><creatorcontrib>Wang, Yi</creatorcontrib><creatorcontrib>Li, Xiaoqing</creatorcontrib><creatorcontrib>Guo, Yuxia</creatorcontrib><creatorcontrib>Liang, Shaoyan</creatorcontrib><title>HA117 endows HL60 cells with a stem-like signature by inhibiting the degradation of DNMT1 via its ability to down-regulate expression of the GGL domain of RGS6</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>All-trans retinoic acid (ATRA) induces complete remission in almost all patients with acute promyelocytic leukemia (APL) via its ability to induce the in vivo differentiation of APL blasts. However, prolonged ATRA treatment can result in drug resistance. In previous studies, we generated a multi-drug-resistant HL60/ATRA cell line and found it to contain a new drug resistance-related gene segment, HA117. In this study, we demonstrate that ATRA induces multi-drug-resistant subpopulations of HL60 cells with a putative stem-like signature by up-regulating the expression of the new gene segment HA117. Western blot analysis and quantitative real-time PCR demonstrated that HA117 causes alternative splicing of regulator of G-protein signaling 6 (RGS6) and down-regulation of the expression of the GGL domain of RGS6, which plays an important role in DNA methyltransferase 1 (DNMT1) degradation. Moreover, DNMT1 expression was increased in multi-drug resistance HL60/ATRA cells. Knockdown of HA117 restored expression of the GGL domain and blocked DNMT1 expression. Moreover, resistant cells displayed a putative stem-like signature with increased expression of cancer steam cell markers CD133 and CD123. The stem cell marker, Nanog, was significantly up-regulated. In conclusion, our study shows that HA117 potentially promotes the stem-like signature of the HL60/ATRA cell line by inhibiting by the ubiquitination and degradation of DNMT1 and by down-regulating the expression of the GGL domain of RGS6. These results throw light on the cellular events associated with the ATRA-induced multi-drug resistance phenotype in acute leukemia.</description><subject>Acute myelocytic leukemia</subject><subject>Acute promyeloid leukemia</subject><subject>Alternative splicing</subject><subject>APL (programming language)</subject><subject>Binding sites</subject><subject>Biology and life sciences</subject><subject>Brain cancer</subject><subject>Cancer</subject><subject>Cancer therapies</subject><subject>CD123 antigen</subject><subject>Cell cycle</subject><subject>Child development</subject><subject>Children & youth</subject><subject>Cooperation</subject><subject>Degradation</subject><subject>Deoxyribonucleic acid</subject><subject>Differentiation</subject><subject>DNA</subject><subject>DNA methylation</subject><subject>DNA methyltransferase</subject><subject>DNMT1 protein</subject><subject>Down-Regulation</subject><subject>Drug resistance</subject><subject>Drug Resistance, Neoplasm</subject><subject>Drug therapy</subject><subject>Education</subject><subject>Epigenetics</subject><subject>Gastrointestinal surgery</subject><subject>Gene expression</subject><subject>Genes</subject><subject>Genetic aspects</subject><subject>HL-60 Cells</subject><subject>Humans</subject><subject>Laboratories</subject><subject>Leukemia</subject><subject>Leukemia, Promyelocytic, Acute - drug therapy</subject><subject>Leukemia, Promyelocytic, Acute - pathology</subject><subject>Markers</subject><subject>Medicine and Health Sciences</subject><subject>Multidrug resistance</subject><subject>Neoplasm Proteins - physiology</subject><subject>Neoplastic Stem Cells - metabolism</subject><subject>Neoplastic Stem Cells - pathology</subject><subject>Patients</subject><subject>Pediatrics</subject><subject>Physiological aspects</subject><subject>Polymerase chain reaction</subject><subject>Promyeloid leukemia</subject><subject>Proteins</subject><subject>Proteolysis</subject><subject>Real time</subject><subject>Remission</subject><subject>Repressor Proteins - metabolism</subject><subject>Research and analysis methods</subject><subject>Retinoic acid</subject><subject>RGS Proteins - chemistry</subject><subject>RGS Proteins - metabolism</subject><subject>Science</subject><subject>Steam</subject><subject>Stem cells</subject><subject>Subpopulations</subject><subject>Tretinoin</subject><subject>Tretinoin - 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Academic</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Li, Shuangshuang</au><au>Jin, Xianqing</au><au>Wu, Huan</au><au>Wang, Yi</au><au>Li, Xiaoqing</au><au>Guo, Yuxia</au><au>Liang, Shaoyan</au><au>Ahmad, Aamir</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>HA117 endows HL60 cells with a stem-like signature by inhibiting the degradation of DNMT1 via its ability to down-regulate expression of the GGL domain of RGS6</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2017-06-30</date><risdate>2017</risdate><volume>12</volume><issue>6</issue><spage>e0180142</spage><epage>e0180142</epage><pages>e0180142-e0180142</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>All-trans retinoic acid (ATRA) induces complete remission in almost all patients with acute promyelocytic leukemia (APL) via its ability to induce the in vivo differentiation of APL blasts. However, prolonged ATRA treatment can result in drug resistance. In previous studies, we generated a multi-drug-resistant HL60/ATRA cell line and found it to contain a new drug resistance-related gene segment, HA117. In this study, we demonstrate that ATRA induces multi-drug-resistant subpopulations of HL60 cells with a putative stem-like signature by up-regulating the expression of the new gene segment HA117. Western blot analysis and quantitative real-time PCR demonstrated that HA117 causes alternative splicing of regulator of G-protein signaling 6 (RGS6) and down-regulation of the expression of the GGL domain of RGS6, which plays an important role in DNA methyltransferase 1 (DNMT1) degradation. Moreover, DNMT1 expression was increased in multi-drug resistance HL60/ATRA cells. Knockdown of HA117 restored expression of the GGL domain and blocked DNMT1 expression. Moreover, resistant cells displayed a putative stem-like signature with increased expression of cancer steam cell markers CD133 and CD123. The stem cell marker, Nanog, was significantly up-regulated. In conclusion, our study shows that HA117 potentially promotes the stem-like signature of the HL60/ATRA cell line by inhibiting by the ubiquitination and degradation of DNMT1 and by down-regulating the expression of the GGL domain of RGS6. These results throw light on the cellular events associated with the ATRA-induced multi-drug resistance phenotype in acute leukemia.</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>28665981</pmid><doi>10.1371/journal.pone.0180142</doi><tpages>e0180142</tpages><orcidid>https://orcid.org/0000-0002-6433-8719</orcidid><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2017-06, Vol.12 (6), p.e0180142-e0180142 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1914988490 |
| source | Public Library of Science (PLoS) Journals Open Access; PubMed Central Free; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; Free Full-Text Journals in Chemistry |
| subjects | Acute myelocytic leukemia Acute promyeloid leukemia Alternative splicing APL (programming language) Binding sites Biology and life sciences Brain cancer Cancer Cancer therapies CD123 antigen Cell cycle Child development Children & youth Cooperation Degradation Deoxyribonucleic acid Differentiation DNA DNA methylation DNA methyltransferase DNMT1 protein Down-Regulation Drug resistance Drug Resistance, Neoplasm Drug therapy Education Epigenetics Gastrointestinal surgery Gene expression Genes Genetic aspects HL-60 Cells Humans Laboratories Leukemia Leukemia, Promyelocytic, Acute - drug therapy Leukemia, Promyelocytic, Acute - pathology Markers Medicine and Health Sciences Multidrug resistance Neoplasm Proteins - physiology Neoplastic Stem Cells - metabolism Neoplastic Stem Cells - pathology Patients Pediatrics Physiological aspects Polymerase chain reaction Promyeloid leukemia Proteins Proteolysis Real time Remission Repressor Proteins - metabolism Research and analysis methods Retinoic acid RGS Proteins - chemistry RGS Proteins - metabolism Science Steam Stem cells Subpopulations Tretinoin Tretinoin - pharmacology Tretinoin - therapeutic use Tumors Ubiquitination |
| title | HA117 endows HL60 cells with a stem-like signature by inhibiting the degradation of DNMT1 via its ability to down-regulate expression of the GGL domain of RGS6 |
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