USP22 knockdown enhanced chemosensitivity of hepatocellular carcinoma cells to 5-Fu by up-regulation of Smad4 and suppression of Akt
USP22, a member of the deubiquitinases (DUBs) family, is known to be a key subunit of the human Spt-Ada-Gcn5 acetyltransferase (hSAGA) transcriptional cofactor complex. Within hSAGA, USP22 removes ubiquitin from histone proteins, thus regulating the transcription and expression of downstream genes....
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| Veröffentlicht in: | Oncotarget 2017-04, Vol.8 (15), p.24728-24740 |
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| creator | Zhang, Jing Luo, Nan Tian, Yu Li, Jiazhi Yang, Xiaozhou Yin, Huimin Xiao, Congshu Sheng, Jie Li, Yang Tang, Bo Li, Rongkuan |
| description | USP22, a member of the deubiquitinases (DUBs) family, is known to be a key subunit of the human Spt-Ada-Gcn5 acetyltransferase (hSAGA) transcriptional cofactor complex. Within hSAGA, USP22 removes ubiquitin from histone proteins, thus regulating the transcription and expression of downstream genes. USP22 plays important roles in many cancers; however, its effect and the mechanism underlying HCC chemoresistance remain unclear. In the present study, we found that USP22 was highly expressed in chemoresistant HCC tissues and cells and was correlated with the prognosis of HCC patients who received chemotherapy. Silencing USP22 in chemoresistant HCC Bel/Fu cells dramatically inhibited proliferation, migration, invasion and epithelial-mesenchymal transition in vitro; suppressed tumorigenic and metastatic capacities in vivo; and inhibited drug resistance-related proteins (MDR1, LRP, MRP1). Mechanistically, we found that USP22 knockdown exerts its function through down-regulating PI3K and activating Smad4, which inhibited phosphorylation of Akt. Silencing Smad4 blocked USP22 knockdown-induced Akt inhibition in Bel/Fu cells. Our results, for the first time, provide evidence that USP22 plays a critical role in the development of chemoresistant HCC cells and that high USP22 expression serves as a molecular marker for the prognosis of HCC patients who undergo chemotherapy. |
| doi_str_mv | 10.18632/oncotarget.15798 |
| format | Article |
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Within hSAGA, USP22 removes ubiquitin from histone proteins, thus regulating the transcription and expression of downstream genes. USP22 plays important roles in many cancers; however, its effect and the mechanism underlying HCC chemoresistance remain unclear. In the present study, we found that USP22 was highly expressed in chemoresistant HCC tissues and cells and was correlated with the prognosis of HCC patients who received chemotherapy. Silencing USP22 in chemoresistant HCC Bel/Fu cells dramatically inhibited proliferation, migration, invasion and epithelial-mesenchymal transition in vitro; suppressed tumorigenic and metastatic capacities in vivo; and inhibited drug resistance-related proteins (MDR1, LRP, MRP1). Mechanistically, we found that USP22 knockdown exerts its function through down-regulating PI3K and activating Smad4, which inhibited phosphorylation of Akt. Silencing Smad4 blocked USP22 knockdown-induced Akt inhibition in Bel/Fu cells. Our results, for the first time, provide evidence that USP22 plays a critical role in the development of chemoresistant HCC cells and that high USP22 expression serves as a molecular marker for the prognosis of HCC patients who undergo chemotherapy.</description><identifier>ISSN: 1949-2553</identifier><identifier>EISSN: 1949-2553</identifier><identifier>DOI: 10.18632/oncotarget.15798</identifier><identifier>PMID: 28445968</identifier><language>eng</language><publisher>United States: Impact Journals LLC</publisher><subject>Animals ; Carcinoma, Hepatocellular - drug therapy ; Carcinoma, Hepatocellular - metabolism ; Carcinoma, Hepatocellular - pathology ; Cell Line, Tumor ; Cell Proliferation - drug effects ; Drug Resistance, Neoplasm ; Female ; Fluorouracil - pharmacology ; Fluorouracil - therapeutic use ; Gene Knockdown Techniques ; Hep G2 Cells ; Humans ; Liver Neoplasms - drug therapy ; Liver Neoplasms - metabolism ; Liver Neoplasms - pathology ; Male ; Mice ; Mice, Nude ; Middle Aged ; Prognosis ; Proto-Oncogene Proteins c-akt - antagonists & inhibitors ; Proto-Oncogene Proteins c-akt - metabolism ; Research Paper ; Smad4 Protein - genetics ; Smad4 Protein - metabolism ; Thiolester Hydrolases - biosynthesis ; Thiolester Hydrolases - deficiency ; Thiolester Hydrolases - metabolism ; Up-Regulation - drug effects ; Xenograft Model Antitumor Assays</subject><ispartof>Oncotarget, 2017-04, Vol.8 (15), p.24728-24740</ispartof><rights>Copyright: © 2017 Zhang et al. 2017</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c356t-b62cba4e33a2974f74c129358d2836b749b6abf308643ee9fa8f411b70e1b94b3</citedby><cites>FETCH-LOGICAL-c356t-b62cba4e33a2974f74c129358d2836b749b6abf308643ee9fa8f411b70e1b94b3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5421883/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC5421883/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28445968$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhang, Jing</creatorcontrib><creatorcontrib>Luo, Nan</creatorcontrib><creatorcontrib>Tian, Yu</creatorcontrib><creatorcontrib>Li, Jiazhi</creatorcontrib><creatorcontrib>Yang, Xiaozhou</creatorcontrib><creatorcontrib>Yin, Huimin</creatorcontrib><creatorcontrib>Xiao, Congshu</creatorcontrib><creatorcontrib>Sheng, Jie</creatorcontrib><creatorcontrib>Li, Yang</creatorcontrib><creatorcontrib>Tang, Bo</creatorcontrib><creatorcontrib>Li, Rongkuan</creatorcontrib><title>USP22 knockdown enhanced chemosensitivity of hepatocellular carcinoma cells to 5-Fu by up-regulation of Smad4 and suppression of Akt</title><title>Oncotarget</title><addtitle>Oncotarget</addtitle><description>USP22, a member of the deubiquitinases (DUBs) family, is known to be a key subunit of the human Spt-Ada-Gcn5 acetyltransferase (hSAGA) transcriptional cofactor complex. Within hSAGA, USP22 removes ubiquitin from histone proteins, thus regulating the transcription and expression of downstream genes. USP22 plays important roles in many cancers; however, its effect and the mechanism underlying HCC chemoresistance remain unclear. In the present study, we found that USP22 was highly expressed in chemoresistant HCC tissues and cells and was correlated with the prognosis of HCC patients who received chemotherapy. Silencing USP22 in chemoresistant HCC Bel/Fu cells dramatically inhibited proliferation, migration, invasion and epithelial-mesenchymal transition in vitro; suppressed tumorigenic and metastatic capacities in vivo; and inhibited drug resistance-related proteins (MDR1, LRP, MRP1). Mechanistically, we found that USP22 knockdown exerts its function through down-regulating PI3K and activating Smad4, which inhibited phosphorylation of Akt. Silencing Smad4 blocked USP22 knockdown-induced Akt inhibition in Bel/Fu cells. Our results, for the first time, provide evidence that USP22 plays a critical role in the development of chemoresistant HCC cells and that high USP22 expression serves as a molecular marker for the prognosis of HCC patients who undergo chemotherapy.</description><subject>Animals</subject><subject>Carcinoma, Hepatocellular - drug therapy</subject><subject>Carcinoma, Hepatocellular - metabolism</subject><subject>Carcinoma, Hepatocellular - pathology</subject><subject>Cell Line, Tumor</subject><subject>Cell Proliferation - drug effects</subject><subject>Drug Resistance, Neoplasm</subject><subject>Female</subject><subject>Fluorouracil - pharmacology</subject><subject>Fluorouracil - therapeutic use</subject><subject>Gene Knockdown Techniques</subject><subject>Hep G2 Cells</subject><subject>Humans</subject><subject>Liver Neoplasms - drug therapy</subject><subject>Liver Neoplasms - metabolism</subject><subject>Liver Neoplasms - pathology</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Nude</subject><subject>Middle Aged</subject><subject>Prognosis</subject><subject>Proto-Oncogene Proteins c-akt - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins c-akt - metabolism</subject><subject>Research Paper</subject><subject>Smad4 Protein - genetics</subject><subject>Smad4 Protein - metabolism</subject><subject>Thiolester Hydrolases - biosynthesis</subject><subject>Thiolester Hydrolases - deficiency</subject><subject>Thiolester Hydrolases - metabolism</subject><subject>Up-Regulation - drug effects</subject><subject>Xenograft Model Antitumor Assays</subject><issn>1949-2553</issn><issn>1949-2553</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpVUU1P3DAQtaqigoAfwKXysZfQ-CuxL5UQKm0lpCIBZ8t2JrvuJnZqO6C994c3C1sKc5nRzHtvZvQQOiP1OZENo59jcLGYtIJyTkSr5Dt0RBRXFRWCvX9VH6LTnH_VSwjeSqo-oEMqOReqkUfoz_3tDaV4E6LbdPExYAhrExx02K1hjBlC9sU_-LLFscdrmEyJDoZhHkzCziTnQxwN3rUyLhGL6mrGdovnqUqwWlDFx7Cj3o6m49iEDud5mhLkvB9cbMoJOujNkOF0n4_R_dXXu8vv1fXPbz8uL64rx0RTKttQZw0HxgxVLe9b7ghVTMiOStbYlivbGNuzWjacAajeyJ4TYtsaiFXcsmP05Vl3mu0InYNQkhn0lPxo0lZH4_XbSfBrvYoPWnBKpGSLwKe9QIq_Z8hFjz7vfjcB4pw1kYq2VDDeLlDyDHUp5pygf1lDav1koP5voH4ycOF8fH3fC-OfXewvCCOclQ</recordid><startdate>20170411</startdate><enddate>20170411</enddate><creator>Zhang, Jing</creator><creator>Luo, Nan</creator><creator>Tian, Yu</creator><creator>Li, Jiazhi</creator><creator>Yang, Xiaozhou</creator><creator>Yin, Huimin</creator><creator>Xiao, Congshu</creator><creator>Sheng, Jie</creator><creator>Li, Yang</creator><creator>Tang, Bo</creator><creator>Li, Rongkuan</creator><general>Impact Journals LLC</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>7X8</scope><scope>5PM</scope></search><sort><creationdate>20170411</creationdate><title>USP22 knockdown enhanced chemosensitivity of hepatocellular carcinoma cells to 5-Fu by up-regulation of Smad4 and suppression of Akt</title><author>Zhang, Jing ; Luo, Nan ; Tian, Yu ; Li, Jiazhi ; Yang, Xiaozhou ; Yin, Huimin ; Xiao, Congshu ; Sheng, Jie ; Li, Yang ; Tang, Bo ; Li, Rongkuan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-b62cba4e33a2974f74c129358d2836b749b6abf308643ee9fa8f411b70e1b94b3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Animals</topic><topic>Carcinoma, Hepatocellular - drug therapy</topic><topic>Carcinoma, Hepatocellular - metabolism</topic><topic>Carcinoma, Hepatocellular - pathology</topic><topic>Cell Line, Tumor</topic><topic>Cell Proliferation - drug effects</topic><topic>Drug Resistance, Neoplasm</topic><topic>Female</topic><topic>Fluorouracil - pharmacology</topic><topic>Fluorouracil - therapeutic use</topic><topic>Gene Knockdown Techniques</topic><topic>Hep G2 Cells</topic><topic>Humans</topic><topic>Liver Neoplasms - drug therapy</topic><topic>Liver Neoplasms - metabolism</topic><topic>Liver Neoplasms - pathology</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Nude</topic><topic>Middle Aged</topic><topic>Prognosis</topic><topic>Proto-Oncogene Proteins c-akt - antagonists & inhibitors</topic><topic>Proto-Oncogene Proteins c-akt - metabolism</topic><topic>Research Paper</topic><topic>Smad4 Protein - genetics</topic><topic>Smad4 Protein - metabolism</topic><topic>Thiolester Hydrolases - biosynthesis</topic><topic>Thiolester Hydrolases - deficiency</topic><topic>Thiolester Hydrolases - metabolism</topic><topic>Up-Regulation - drug effects</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>online_resources</toplevel><creatorcontrib>Zhang, Jing</creatorcontrib><creatorcontrib>Luo, Nan</creatorcontrib><creatorcontrib>Tian, Yu</creatorcontrib><creatorcontrib>Li, Jiazhi</creatorcontrib><creatorcontrib>Yang, Xiaozhou</creatorcontrib><creatorcontrib>Yin, Huimin</creatorcontrib><creatorcontrib>Xiao, Congshu</creatorcontrib><creatorcontrib>Sheng, Jie</creatorcontrib><creatorcontrib>Li, Yang</creatorcontrib><creatorcontrib>Tang, Bo</creatorcontrib><creatorcontrib>Li, Rongkuan</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Oncotarget</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zhang, Jing</au><au>Luo, Nan</au><au>Tian, Yu</au><au>Li, Jiazhi</au><au>Yang, Xiaozhou</au><au>Yin, Huimin</au><au>Xiao, Congshu</au><au>Sheng, Jie</au><au>Li, Yang</au><au>Tang, Bo</au><au>Li, Rongkuan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>USP22 knockdown enhanced chemosensitivity of hepatocellular carcinoma cells to 5-Fu by up-regulation of Smad4 and suppression of Akt</atitle><jtitle>Oncotarget</jtitle><addtitle>Oncotarget</addtitle><date>2017-04-11</date><risdate>2017</risdate><volume>8</volume><issue>15</issue><spage>24728</spage><epage>24740</epage><pages>24728-24740</pages><issn>1949-2553</issn><eissn>1949-2553</eissn><abstract>USP22, a member of the deubiquitinases (DUBs) family, is known to be a key subunit of the human Spt-Ada-Gcn5 acetyltransferase (hSAGA) transcriptional cofactor complex. Within hSAGA, USP22 removes ubiquitin from histone proteins, thus regulating the transcription and expression of downstream genes. USP22 plays important roles in many cancers; however, its effect and the mechanism underlying HCC chemoresistance remain unclear. In the present study, we found that USP22 was highly expressed in chemoresistant HCC tissues and cells and was correlated with the prognosis of HCC patients who received chemotherapy. Silencing USP22 in chemoresistant HCC Bel/Fu cells dramatically inhibited proliferation, migration, invasion and epithelial-mesenchymal transition in vitro; suppressed tumorigenic and metastatic capacities in vivo; and inhibited drug resistance-related proteins (MDR1, LRP, MRP1). Mechanistically, we found that USP22 knockdown exerts its function through down-regulating PI3K and activating Smad4, which inhibited phosphorylation of Akt. Silencing Smad4 blocked USP22 knockdown-induced Akt inhibition in Bel/Fu cells. Our results, for the first time, provide evidence that USP22 plays a critical role in the development of chemoresistant HCC cells and that high USP22 expression serves as a molecular marker for the prognosis of HCC patients who undergo chemotherapy.</abstract><cop>United States</cop><pub>Impact Journals LLC</pub><pmid>28445968</pmid><doi>10.18632/oncotarget.15798</doi><tpages>13</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Carcinoma, Hepatocellular - drug therapy Carcinoma, Hepatocellular - metabolism Carcinoma, Hepatocellular - pathology Cell Line, Tumor Cell Proliferation - drug effects Drug Resistance, Neoplasm Female Fluorouracil - pharmacology Fluorouracil - therapeutic use Gene Knockdown Techniques Hep G2 Cells Humans Liver Neoplasms - drug therapy Liver Neoplasms - metabolism Liver Neoplasms - pathology Male Mice Mice, Nude Middle Aged Prognosis Proto-Oncogene Proteins c-akt - antagonists & inhibitors Proto-Oncogene Proteins c-akt - metabolism Research Paper Smad4 Protein - genetics Smad4 Protein - metabolism Thiolester Hydrolases - biosynthesis Thiolester Hydrolases - deficiency Thiolester Hydrolases - metabolism Up-Regulation - drug effects Xenograft Model Antitumor Assays |
| title | USP22 knockdown enhanced chemosensitivity of hepatocellular carcinoma cells to 5-Fu by up-regulation of Smad4 and suppression of Akt |
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