Nuclear translocation of ISG15 regulated by PPP2R2B inhibits cisplatin resistance of bladder cancer
Cisplatin resistance is a major challenge for systemic therapy against advanced bladder cancer (BC). Little information is available on the regulation of cisplatin resistance and the underlying mechanisms require elucidation. Here, we detected that downregulation of the tumor suppressor, PPP2R2B (a...
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| creator | Huang, Gaowei Liu, Jinwen Yu, Anze Luo, Chenggong Zhu, Jiangquan Wang, Yinghan Dai, Ziran Zhang, Lizhen Feng, Zihao Lu, Jun Dong, Zhong Luo, Junhang Chen, Wei Chen, Zhenhua |
| description | Cisplatin resistance is a major challenge for systemic therapy against advanced bladder cancer (BC). Little information is available on the regulation of cisplatin resistance and the underlying mechanisms require elucidation. Here, we detected that downregulation of the tumor suppressor, PPP2R2B (a serine/threonine protein phosphatase 2 A regulatory subunit), in BC promoted cell proliferation and migration. What’s more, low PPP2R2B expression was correlated with cisplatin resistance. In vitro and in vivo experiments verified that PPP2R2B could promote BC sensitivity to cisplatin. In terms of mechanism, we identified a novel function of PPP2R2B as a nucleocytoplasmic transport molecule. PPP2R2B promoted ISG15 entry into the nucleus by mediating binding of IPO5 with ISG15. Nuclear translocation of ISG15 inhibited DNA repair, further increasing ISG15 expression through activation of the STING pathway. Besides, PPP2R2B was down-regulated by SUV39H1-mediated histone 3 lysine 9 trimethylation, which could be restored by the SUV39H1-specific inhibitor, chaetocin. Our data suggest that PPP2R2B expression level is a potential biomarker for chemotherapy response and that chemotherapy in combination with chaetocin may be a feasible treatment strategy for patients with BC. |
| doi_str_mv | 10.1007/s00018-024-05320-1 |
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Little information is available on the regulation of cisplatin resistance and the underlying mechanisms require elucidation. Here, we detected that downregulation of the tumor suppressor, PPP2R2B (a serine/threonine protein phosphatase 2 A regulatory subunit), in BC promoted cell proliferation and migration. What’s more, low PPP2R2B expression was correlated with cisplatin resistance. In vitro and in vivo experiments verified that PPP2R2B could promote BC sensitivity to cisplatin. In terms of mechanism, we identified a novel function of PPP2R2B as a nucleocytoplasmic transport molecule. PPP2R2B promoted ISG15 entry into the nucleus by mediating binding of IPO5 with ISG15. Nuclear translocation of ISG15 inhibited DNA repair, further increasing ISG15 expression through activation of the STING pathway. Besides, PPP2R2B was down-regulated by SUV39H1-mediated histone 3 lysine 9 trimethylation, which could be restored by the SUV39H1-specific inhibitor, chaetocin. Our data suggest that PPP2R2B expression level is a potential biomarker for chemotherapy response and that chemotherapy in combination with chaetocin may be a feasible treatment strategy for patients with BC.</description><identifier>ISSN: 1420-682X</identifier><identifier>ISSN: 1420-9071</identifier><identifier>EISSN: 1420-9071</identifier><identifier>DOI: 10.1007/s00018-024-05320-1</identifier><identifier>PMID: 38976080</identifier><language>eng</language><publisher>Cham: Springer International Publishing</publisher><subject>Animals ; Antineoplastic Agents - pharmacology ; Biochemistry ; Biomarkers ; Biomedical and Life Sciences ; Biomedicine ; Bladder ; Bladder cancer ; Cancer ; Cell Biology ; Cell Line, Tumor ; Cell migration ; Cell Movement - drug effects ; Cell Nucleus - metabolism ; Cell proliferation ; Cell Proliferation - drug effects ; Chemotherapy ; Cisplatin ; Cisplatin - pharmacology ; Cytokines - metabolism ; DNA repair ; Drug Resistance, Neoplasm - drug effects ; Drug Resistance, Neoplasm - genetics ; drug therapy ; Female ; Gene expression ; Gene Expression Regulation, Neoplastic - drug effects ; Histones ; Humans ; Life Sciences ; Lysine ; Methylation ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Nerve Tissue Proteins ; Nuclear transport ; nucleocytoplasmic transport ; Original ; Original Article ; Protein phosphatase ; Protein Phosphatase 2 - genetics ; Protein Phosphatase 2 - metabolism ; serine ; threonine ; Translocation ; Tumor suppressor genes ; Ubiquitins - genetics ; Ubiquitins - metabolism ; urinary bladder neoplasms ; Urinary Bladder Neoplasms - drug therapy ; Urinary Bladder Neoplasms - genetics ; Urinary Bladder Neoplasms - metabolism ; Urinary Bladder Neoplasms - pathology</subject><ispartof>Cellular and molecular life sciences : CMLS, 2024-12, Vol.81 (1), p.292-292, Article 292</ispartof><rights>The Author(s) 2024</rights><rights>2024. The Author(s).</rights><rights>The Author(s) 2024. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c345t-f044ec45c1d9db96e3f0faaffd2fde39c1a522499c97d14a99de076eaa839c073</cites><orcidid>0000-0002-8889-5122</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/PMC11335216/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC11335216/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,41096,41464,42165,42533,51294,51551,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/38976080$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Huang, Gaowei</creatorcontrib><creatorcontrib>Liu, Jinwen</creatorcontrib><creatorcontrib>Yu, Anze</creatorcontrib><creatorcontrib>Luo, Chenggong</creatorcontrib><creatorcontrib>Zhu, Jiangquan</creatorcontrib><creatorcontrib>Wang, Yinghan</creatorcontrib><creatorcontrib>Dai, Ziran</creatorcontrib><creatorcontrib>Zhang, Lizhen</creatorcontrib><creatorcontrib>Feng, Zihao</creatorcontrib><creatorcontrib>Lu, Jun</creatorcontrib><creatorcontrib>Dong, Zhong</creatorcontrib><creatorcontrib>Luo, Junhang</creatorcontrib><creatorcontrib>Chen, Wei</creatorcontrib><creatorcontrib>Chen, Zhenhua</creatorcontrib><title>Nuclear translocation of ISG15 regulated by PPP2R2B inhibits cisplatin resistance of bladder cancer</title><title>Cellular and molecular life sciences : CMLS</title><addtitle>Cell. Mol. Life Sci</addtitle><addtitle>Cell Mol Life Sci</addtitle><description>Cisplatin resistance is a major challenge for systemic therapy against advanced bladder cancer (BC). Little information is available on the regulation of cisplatin resistance and the underlying mechanisms require elucidation. Here, we detected that downregulation of the tumor suppressor, PPP2R2B (a serine/threonine protein phosphatase 2 A regulatory subunit), in BC promoted cell proliferation and migration. What’s more, low PPP2R2B expression was correlated with cisplatin resistance. In vitro and in vivo experiments verified that PPP2R2B could promote BC sensitivity to cisplatin. In terms of mechanism, we identified a novel function of PPP2R2B as a nucleocytoplasmic transport molecule. PPP2R2B promoted ISG15 entry into the nucleus by mediating binding of IPO5 with ISG15. Nuclear translocation of ISG15 inhibited DNA repair, further increasing ISG15 expression through activation of the STING pathway. Besides, PPP2R2B was down-regulated by SUV39H1-mediated histone 3 lysine 9 trimethylation, which could be restored by the SUV39H1-specific inhibitor, chaetocin. Our data suggest that PPP2R2B expression level is a potential biomarker for chemotherapy response and that chemotherapy in combination with chaetocin may be a feasible treatment strategy for patients with BC.</description><subject>Animals</subject><subject>Antineoplastic Agents - pharmacology</subject><subject>Biochemistry</subject><subject>Biomarkers</subject><subject>Biomedical and Life Sciences</subject><subject>Biomedicine</subject><subject>Bladder</subject><subject>Bladder cancer</subject><subject>Cancer</subject><subject>Cell Biology</subject><subject>Cell Line, Tumor</subject><subject>Cell migration</subject><subject>Cell Movement - drug effects</subject><subject>Cell Nucleus - metabolism</subject><subject>Cell proliferation</subject><subject>Cell Proliferation - drug effects</subject><subject>Chemotherapy</subject><subject>Cisplatin</subject><subject>Cisplatin - pharmacology</subject><subject>Cytokines - metabolism</subject><subject>DNA repair</subject><subject>Drug Resistance, Neoplasm - drug effects</subject><subject>Drug Resistance, Neoplasm - genetics</subject><subject>drug therapy</subject><subject>Female</subject><subject>Gene expression</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Histones</subject><subject>Humans</subject><subject>Life Sciences</subject><subject>Lysine</subject><subject>Methylation</subject><subject>Mice</subject><subject>Mice, Inbred BALB C</subject><subject>Mice, Nude</subject><subject>Nerve Tissue Proteins</subject><subject>Nuclear transport</subject><subject>nucleocytoplasmic transport</subject><subject>Original</subject><subject>Original Article</subject><subject>Protein phosphatase</subject><subject>Protein Phosphatase 2 - genetics</subject><subject>Protein Phosphatase 2 - metabolism</subject><subject>serine</subject><subject>threonine</subject><subject>Translocation</subject><subject>Tumor suppressor genes</subject><subject>Ubiquitins - genetics</subject><subject>Ubiquitins - metabolism</subject><subject>urinary bladder neoplasms</subject><subject>Urinary Bladder Neoplasms - drug therapy</subject><subject>Urinary Bladder Neoplasms - genetics</subject><subject>Urinary Bladder Neoplasms - metabolism</subject><subject>Urinary Bladder Neoplasms - pathology</subject><issn>1420-682X</issn><issn>1420-9071</issn><issn>1420-9071</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>C6C</sourceid><sourceid>EIF</sourceid><recordid>eNqFkUuPFCEUhYnROOPoH3BhSNy4KeVRxWNldKLjJBPt-EjcEQouPUyqoYUqk_n30tPt-FhoWEA43z3cy0HoMSXPKSHyRSWEUNUR1ndk4Ix09A46pn07aCLp3cNZKPb1CD2o9arRg2LiPjriSktBFDlG7v3iJrAFz8WmOmVn55gTzgGffzqjAy6wXiY7g8fjNV6tVuwje41juoxjnCt2sW6bGlPjaqyzTQ52teNkvYeC3e6iPET3gp0qPDrsJ-jL2zefT991Fx_Ozk9fXXSO98PcBdL34PrBUa_9qAXwQIK1IXgWPHDtqB0Y67V2WnraW609ECnAWtVEIvkJern33S7jBryD1IaazLbEjS3XJtto_lRSvDTr_N1QyvnAqGgOzw4OJX9boM5mE6uDabIJ8lINpwMXUivB_o-21tpiUjf06V_oVV5Kal9xQymmpNhRbE-5kmstEG4bp8Ts8jb7vE3L29zkbWgrevL7yLclPwNuAN8DtUlpDeXX2_-w_QG-NrZT</recordid><startdate>20241201</startdate><enddate>20241201</enddate><creator>Huang, Gaowei</creator><creator>Liu, Jinwen</creator><creator>Yu, Anze</creator><creator>Luo, Chenggong</creator><creator>Zhu, Jiangquan</creator><creator>Wang, Yinghan</creator><creator>Dai, Ziran</creator><creator>Zhang, Lizhen</creator><creator>Feng, Zihao</creator><creator>Lu, Jun</creator><creator>Dong, Zhong</creator><creator>Luo, Junhang</creator><creator>Chen, Wei</creator><creator>Chen, Zhenhua</creator><general>Springer International Publishing</general><general>Springer Nature B.V</general><scope>C6C</scope><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>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SS</scope><scope>7T5</scope><scope>7T7</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U7</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>7S9</scope><scope>L.6</scope><scope>5PM</scope><orcidid>https://orcid.org/0000-0002-8889-5122</orcidid></search><sort><creationdate>20241201</creationdate><title>Nuclear translocation of ISG15 regulated by PPP2R2B inhibits cisplatin resistance of bladder cancer</title><author>Huang, Gaowei ; Liu, Jinwen ; Yu, Anze ; Luo, Chenggong ; Zhu, Jiangquan ; Wang, Yinghan ; Dai, Ziran ; Zhang, Lizhen ; Feng, Zihao ; Lu, Jun ; Dong, Zhong ; Luo, Junhang ; Chen, Wei ; Chen, Zhenhua</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c345t-f044ec45c1d9db96e3f0faaffd2fde39c1a522499c97d14a99de076eaa839c073</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Animals</topic><topic>Antineoplastic Agents - pharmacology</topic><topic>Biochemistry</topic><topic>Biomarkers</topic><topic>Biomedical and Life Sciences</topic><topic>Biomedicine</topic><topic>Bladder</topic><topic>Bladder cancer</topic><topic>Cancer</topic><topic>Cell Biology</topic><topic>Cell Line, Tumor</topic><topic>Cell migration</topic><topic>Cell Movement - drug effects</topic><topic>Cell Nucleus - metabolism</topic><topic>Cell proliferation</topic><topic>Cell Proliferation - drug effects</topic><topic>Chemotherapy</topic><topic>Cisplatin</topic><topic>Cisplatin - pharmacology</topic><topic>Cytokines - metabolism</topic><topic>DNA repair</topic><topic>Drug Resistance, Neoplasm - drug effects</topic><topic>Drug Resistance, Neoplasm - genetics</topic><topic>drug therapy</topic><topic>Female</topic><topic>Gene expression</topic><topic>Gene Expression Regulation, Neoplastic - drug effects</topic><topic>Histones</topic><topic>Humans</topic><topic>Life Sciences</topic><topic>Lysine</topic><topic>Methylation</topic><topic>Mice</topic><topic>Mice, Inbred BALB C</topic><topic>Mice, Nude</topic><topic>Nerve Tissue Proteins</topic><topic>Nuclear transport</topic><topic>nucleocytoplasmic transport</topic><topic>Original</topic><topic>Original Article</topic><topic>Protein phosphatase</topic><topic>Protein Phosphatase 2 - genetics</topic><topic>Protein Phosphatase 2 - metabolism</topic><topic>serine</topic><topic>threonine</topic><topic>Translocation</topic><topic>Tumor suppressor genes</topic><topic>Ubiquitins - genetics</topic><topic>Ubiquitins - metabolism</topic><topic>urinary bladder neoplasms</topic><topic>Urinary Bladder Neoplasms - drug therapy</topic><topic>Urinary Bladder Neoplasms - genetics</topic><topic>Urinary Bladder Neoplasms - metabolism</topic><topic>Urinary Bladder Neoplasms - pathology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Huang, Gaowei</creatorcontrib><creatorcontrib>Liu, Jinwen</creatorcontrib><creatorcontrib>Yu, Anze</creatorcontrib><creatorcontrib>Luo, Chenggong</creatorcontrib><creatorcontrib>Zhu, Jiangquan</creatorcontrib><creatorcontrib>Wang, Yinghan</creatorcontrib><creatorcontrib>Dai, Ziran</creatorcontrib><creatorcontrib>Zhang, Lizhen</creatorcontrib><creatorcontrib>Feng, Zihao</creatorcontrib><creatorcontrib>Lu, Jun</creatorcontrib><creatorcontrib>Dong, Zhong</creatorcontrib><creatorcontrib>Luo, Junhang</creatorcontrib><creatorcontrib>Chen, Wei</creatorcontrib><creatorcontrib>Chen, Zhenhua</creatorcontrib><collection>Springer Nature OA Free Journals</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Chemoreception Abstracts</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>Industrial and Applied Microbiology Abstracts (Microbiology A)</collection><collection>Neurosciences Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Environmental Sciences and Pollution Management</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - 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Mol. Life Sci</stitle><addtitle>Cell Mol Life Sci</addtitle><date>2024-12-01</date><risdate>2024</risdate><volume>81</volume><issue>1</issue><spage>292</spage><epage>292</epage><pages>292-292</pages><artnum>292</artnum><issn>1420-682X</issn><issn>1420-9071</issn><eissn>1420-9071</eissn><abstract>Cisplatin resistance is a major challenge for systemic therapy against advanced bladder cancer (BC). Little information is available on the regulation of cisplatin resistance and the underlying mechanisms require elucidation. Here, we detected that downregulation of the tumor suppressor, PPP2R2B (a serine/threonine protein phosphatase 2 A regulatory subunit), in BC promoted cell proliferation and migration. What’s more, low PPP2R2B expression was correlated with cisplatin resistance. In vitro and in vivo experiments verified that PPP2R2B could promote BC sensitivity to cisplatin. In terms of mechanism, we identified a novel function of PPP2R2B as a nucleocytoplasmic transport molecule. PPP2R2B promoted ISG15 entry into the nucleus by mediating binding of IPO5 with ISG15. Nuclear translocation of ISG15 inhibited DNA repair, further increasing ISG15 expression through activation of the STING pathway. Besides, PPP2R2B was down-regulated by SUV39H1-mediated histone 3 lysine 9 trimethylation, which could be restored by the SUV39H1-specific inhibitor, chaetocin. Our data suggest that PPP2R2B expression level is a potential biomarker for chemotherapy response and that chemotherapy in combination with chaetocin may be a feasible treatment strategy for patients with BC.</abstract><cop>Cham</cop><pub>Springer International Publishing</pub><pmid>38976080</pmid><doi>10.1007/s00018-024-05320-1</doi><tpages>1</tpages><orcidid>https://orcid.org/0000-0002-8889-5122</orcidid><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Antineoplastic Agents - pharmacology Biochemistry Biomarkers Biomedical and Life Sciences Biomedicine Bladder Bladder cancer Cancer Cell Biology Cell Line, Tumor Cell migration Cell Movement - drug effects Cell Nucleus - metabolism Cell proliferation Cell Proliferation - drug effects Chemotherapy Cisplatin Cisplatin - pharmacology Cytokines - metabolism DNA repair Drug Resistance, Neoplasm - drug effects Drug Resistance, Neoplasm - genetics drug therapy Female Gene expression Gene Expression Regulation, Neoplastic - drug effects Histones Humans Life Sciences Lysine Methylation Mice Mice, Inbred BALB C Mice, Nude Nerve Tissue Proteins Nuclear transport nucleocytoplasmic transport Original Original Article Protein phosphatase Protein Phosphatase 2 - genetics Protein Phosphatase 2 - metabolism serine threonine Translocation Tumor suppressor genes Ubiquitins - genetics Ubiquitins - metabolism urinary bladder neoplasms Urinary Bladder Neoplasms - drug therapy Urinary Bladder Neoplasms - genetics Urinary Bladder Neoplasms - metabolism Urinary Bladder Neoplasms - pathology |
| title | Nuclear translocation of ISG15 regulated by PPP2R2B inhibits cisplatin resistance of bladder cancer |
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