TNFα-induced IDH1 hyperacetylation reprograms redox homeostasis and promotes the chemotherapeutic sensitivity
The heterogeneity and drug resistance of colorectal cancer (CRC) often lead to treatment failure. Isocitrate dehydrogenase 1 (IDH1), a rate-limiting enzyme in the tricarboxylic acid cycle, regulates the intracellular redox environment and mediates tumor cell resistance to chemotherapeutic drugs. The...
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| Veröffentlicht in: | Oncogene 2023-01, Vol.42 (1), p.35-48 |
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| creator | Yang, Hao Zhao, Xiaoping Liu, Jianjun Jin, Mingming Liu, Xiyu Yan, Jun Yao, Xufeng Mao, Xinyi Li, Nan Liang, Beibei Xie, Wei Zhang, Kunchi Zhao, Jian Liu, Liu Huang, Gang |
| description | The heterogeneity and drug resistance of colorectal cancer (CRC) often lead to treatment failure. Isocitrate dehydrogenase 1 (IDH1), a rate-limiting enzyme in the tricarboxylic acid cycle, regulates the intracellular redox environment and mediates tumor cell resistance to chemotherapeutic drugs. The aim of this study was to elucidate the mechanism underlying the involvement of IDH1 acetylation in the development of CRC drug resistance under induction of TNFα. We found TNFα disrupted the interaction between SIRT1 and IDH1 and increased the level of acetylation at K115 of IDH1. Hyperacetylation of K115 was accompanied by protein ubiquitination, which increased its susceptibility to degradation compared to IDH1 K115R. TNFα-mediated hyperacetylation of K115 sensitized the CRC cells to 5FU and reduced the NADPH/NADP ratio to that of intracellular ROS. Furthermore, TNFα and 5FU inhibited CRC tumor growth in vivo, while the K115R-expressing tumor tissues developed 5FU resistance. In human CRC tissues, K115 acetylation was positively correlated with TNFα infiltration, and K115 hyperacetylation was associated with favorable prognosis compared to chemotherapy-induced deacetylation. Therefore, TNFα-induced hyperacetylation at the K115 site of IDH1 promotes antitumor redox homeostasis in CRC cells, and can be used as a marker to predict the response of CRC patients to chemotherapy. |
| doi_str_mv | 10.1038/s41388-022-02528-y |
| format | Article |
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Isocitrate dehydrogenase 1 (IDH1), a rate-limiting enzyme in the tricarboxylic acid cycle, regulates the intracellular redox environment and mediates tumor cell resistance to chemotherapeutic drugs. The aim of this study was to elucidate the mechanism underlying the involvement of IDH1 acetylation in the development of CRC drug resistance under induction of TNFα. We found TNFα disrupted the interaction between SIRT1 and IDH1 and increased the level of acetylation at K115 of IDH1. Hyperacetylation of K115 was accompanied by protein ubiquitination, which increased its susceptibility to degradation compared to IDH1 K115R. TNFα-mediated hyperacetylation of K115 sensitized the CRC cells to 5FU and reduced the NADPH/NADP ratio to that of intracellular ROS. Furthermore, TNFα and 5FU inhibited CRC tumor growth in vivo, while the K115R-expressing tumor tissues developed 5FU resistance. In human CRC tissues, K115 acetylation was positively correlated with TNFα infiltration, and K115 hyperacetylation was associated with favorable prognosis compared to chemotherapy-induced deacetylation. Therefore, TNFα-induced hyperacetylation at the K115 site of IDH1 promotes antitumor redox homeostasis in CRC cells, and can be used as a marker to predict the response of CRC patients to chemotherapy.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/s41388-022-02528-y</identifier><identifier>PMID: 36352097</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>14/19 ; 14/5 ; 38/1 ; 42/109 ; 42/89 ; 59/78 ; 631/67/2327 ; 631/80/458 ; 64/60 ; 82/51 ; 82/80 ; 96/31 ; Acetylation ; Apoptosis ; Cell Biology ; Cell Line, Tumor ; Chemotherapy ; Colorectal cancer ; Colorectal carcinoma ; Deacetylation ; Drug resistance ; Fluorouracil ; Homeostasis ; Human Genetics ; Humans ; Internal Medicine ; Intracellular ; Isocitrate dehydrogenase ; Isocitrate Dehydrogenase - metabolism ; Medicine ; Medicine & Public Health ; Metastases ; Mutation ; Oncology ; Oxidation-Reduction ; SIRT1 protein ; Tricarboxylic acid cycle ; Tumor Necrosis Factor-alpha - metabolism ; Tumor Necrosis Factor-alpha - pharmacology ; Tumor necrosis factor-α ; Tumors ; Ubiquitination</subject><ispartof>Oncogene, 2023-01, Vol.42 (1), p.35-48</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited 2022. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.</rights><rights>2022. The Author(s), under exclusive licence to Springer Nature Limited.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c375t-e7b979fea475d5f8b040bbda130ce5ca28b32f32d271769479dae67dc04dcf403</citedby><cites>FETCH-LOGICAL-c375t-e7b979fea475d5f8b040bbda130ce5ca28b32f32d271769479dae67dc04dcf403</cites><orcidid>0000-0002-8983-4137 ; 0000-0002-5786-7110 ; 0000-0001-8131-8886 ; 0000-0002-3781-7271</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/s41388-022-02528-y$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41388-022-02528-y$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,776,780,27901,27902,41464,42533,51294</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/36352097$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Yang, Hao</creatorcontrib><creatorcontrib>Zhao, Xiaoping</creatorcontrib><creatorcontrib>Liu, Jianjun</creatorcontrib><creatorcontrib>Jin, Mingming</creatorcontrib><creatorcontrib>Liu, Xiyu</creatorcontrib><creatorcontrib>Yan, Jun</creatorcontrib><creatorcontrib>Yao, Xufeng</creatorcontrib><creatorcontrib>Mao, Xinyi</creatorcontrib><creatorcontrib>Li, Nan</creatorcontrib><creatorcontrib>Liang, Beibei</creatorcontrib><creatorcontrib>Xie, Wei</creatorcontrib><creatorcontrib>Zhang, Kunchi</creatorcontrib><creatorcontrib>Zhao, Jian</creatorcontrib><creatorcontrib>Liu, Liu</creatorcontrib><creatorcontrib>Huang, Gang</creatorcontrib><title>TNFα-induced IDH1 hyperacetylation reprograms redox homeostasis and promotes the chemotherapeutic sensitivity</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>The heterogeneity and drug resistance of colorectal cancer (CRC) often lead to treatment failure. Isocitrate dehydrogenase 1 (IDH1), a rate-limiting enzyme in the tricarboxylic acid cycle, regulates the intracellular redox environment and mediates tumor cell resistance to chemotherapeutic drugs. The aim of this study was to elucidate the mechanism underlying the involvement of IDH1 acetylation in the development of CRC drug resistance under induction of TNFα. We found TNFα disrupted the interaction between SIRT1 and IDH1 and increased the level of acetylation at K115 of IDH1. Hyperacetylation of K115 was accompanied by protein ubiquitination, which increased its susceptibility to degradation compared to IDH1 K115R. TNFα-mediated hyperacetylation of K115 sensitized the CRC cells to 5FU and reduced the NADPH/NADP ratio to that of intracellular ROS. Furthermore, TNFα and 5FU inhibited CRC tumor growth in vivo, while the K115R-expressing tumor tissues developed 5FU resistance. In human CRC tissues, K115 acetylation was positively correlated with TNFα infiltration, and K115 hyperacetylation was associated with favorable prognosis compared to chemotherapy-induced deacetylation. Therefore, TNFα-induced hyperacetylation at the K115 site of IDH1 promotes antitumor redox homeostasis in CRC cells, and can be used as a marker to predict the response of CRC patients to chemotherapy.</description><subject>14/19</subject><subject>14/5</subject><subject>38/1</subject><subject>42/109</subject><subject>42/89</subject><subject>59/78</subject><subject>631/67/2327</subject><subject>631/80/458</subject><subject>64/60</subject><subject>82/51</subject><subject>82/80</subject><subject>96/31</subject><subject>Acetylation</subject><subject>Apoptosis</subject><subject>Cell Biology</subject><subject>Cell Line, Tumor</subject><subject>Chemotherapy</subject><subject>Colorectal cancer</subject><subject>Colorectal carcinoma</subject><subject>Deacetylation</subject><subject>Drug resistance</subject><subject>Fluorouracil</subject><subject>Homeostasis</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Internal Medicine</subject><subject>Intracellular</subject><subject>Isocitrate dehydrogenase</subject><subject>Isocitrate Dehydrogenase - 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Academic</collection><jtitle>Oncogene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Yang, Hao</au><au>Zhao, Xiaoping</au><au>Liu, Jianjun</au><au>Jin, Mingming</au><au>Liu, Xiyu</au><au>Yan, Jun</au><au>Yao, Xufeng</au><au>Mao, Xinyi</au><au>Li, Nan</au><au>Liang, Beibei</au><au>Xie, Wei</au><au>Zhang, Kunchi</au><au>Zhao, Jian</au><au>Liu, Liu</au><au>Huang, Gang</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>TNFα-induced IDH1 hyperacetylation reprograms redox homeostasis and promotes the chemotherapeutic sensitivity</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><addtitle>Oncogene</addtitle><date>2023-01-03</date><risdate>2023</risdate><volume>42</volume><issue>1</issue><spage>35</spage><epage>48</epage><pages>35-48</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><abstract>The heterogeneity and drug resistance of colorectal cancer (CRC) often lead to treatment failure. Isocitrate dehydrogenase 1 (IDH1), a rate-limiting enzyme in the tricarboxylic acid cycle, regulates the intracellular redox environment and mediates tumor cell resistance to chemotherapeutic drugs. The aim of this study was to elucidate the mechanism underlying the involvement of IDH1 acetylation in the development of CRC drug resistance under induction of TNFα. We found TNFα disrupted the interaction between SIRT1 and IDH1 and increased the level of acetylation at K115 of IDH1. Hyperacetylation of K115 was accompanied by protein ubiquitination, which increased its susceptibility to degradation compared to IDH1 K115R. TNFα-mediated hyperacetylation of K115 sensitized the CRC cells to 5FU and reduced the NADPH/NADP ratio to that of intracellular ROS. Furthermore, TNFα and 5FU inhibited CRC tumor growth in vivo, while the K115R-expressing tumor tissues developed 5FU resistance. In human CRC tissues, K115 acetylation was positively correlated with TNFα infiltration, and K115 hyperacetylation was associated with favorable prognosis compared to chemotherapy-induced deacetylation. Therefore, TNFα-induced hyperacetylation at the K115 site of IDH1 promotes antitumor redox homeostasis in CRC cells, and can be used as a marker to predict the response of CRC patients to chemotherapy.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>36352097</pmid><doi>10.1038/s41388-022-02528-y</doi><tpages>14</tpages><orcidid>https://orcid.org/0000-0002-8983-4137</orcidid><orcidid>https://orcid.org/0000-0002-5786-7110</orcidid><orcidid>https://orcid.org/0000-0001-8131-8886</orcidid><orcidid>https://orcid.org/0000-0002-3781-7271</orcidid></addata></record> |
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| subjects | 14/19 14/5 38/1 42/109 42/89 59/78 631/67/2327 631/80/458 64/60 82/51 82/80 96/31 Acetylation Apoptosis Cell Biology Cell Line, Tumor Chemotherapy Colorectal cancer Colorectal carcinoma Deacetylation Drug resistance Fluorouracil Homeostasis Human Genetics Humans Internal Medicine Intracellular Isocitrate dehydrogenase Isocitrate Dehydrogenase - metabolism Medicine Medicine & Public Health Metastases Mutation Oncology Oxidation-Reduction SIRT1 protein Tricarboxylic acid cycle Tumor Necrosis Factor-alpha - metabolism Tumor Necrosis Factor-alpha - pharmacology Tumor necrosis factor-α Tumors Ubiquitination |
| title | TNFα-induced IDH1 hyperacetylation reprograms redox homeostasis and promotes the chemotherapeutic sensitivity |
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