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IDH2 contributes to tumorigenesis and poor prognosis by regulating m6A RNA methylation in multiple myeloma
Epigenetic alterations have been previously shown to contribute to multiple myeloma (MM) pathogenesis via DNA methylations and histone modifications. RNA methylation, a novel epigenetic modification, is required for cancer cell survival, and targeting this pathway has been proposed as a new therapeu...
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Published in: | Oncogene 2021-09, Vol.40 (35), p.5393-5402 |
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container_title | Oncogene |
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description | Epigenetic alterations have been previously shown to contribute to multiple myeloma (MM) pathogenesis via DNA methylations and histone modifications. RNA methylation, a novel epigenetic modification, is required for cancer cell survival, and targeting this pathway has been proposed as a new therapeutic strategy. The extent to the N6-methyladenosine (m6A)-regulatory pathway functions in MM remains unknown. Here, we show that an imbalance of RNA methylation may underlies the tumorigenesis of MM. Mechanistically, isocitrate dehydrogenase 2 (IDH2) is highly expressed in CD138
+
cells from MM and its levels appear a progressive increase in the progression of plasma cell dyscrasias. Downregulation of IDH2 increases global m6A RNA levels and reduces myeloma cell growth in vitro, decreases the burden of disease and prolongs overall survival in vivo. IDH2 regulates RNA methylation by activating the RNA demethylase FTO, which is an α-KG-dependent dioxygenase. Furthermore, IDH2-mediated FTO activation decreases the m6A level on WNT7B transcripts, then increases WNT7B expression and thus activated Wnt signaling pathway. Moreover, survival analysis indicates that the elevated expression of IDH2 predicts a poor prognosis. Higher expression of FTO is related to higher International Staging System (ISS) stage and higher Revised-ISS (R-ISS) stage of MM. Collectively, our studies reveal that IDH2 regulates global m6A RNA modification in MM via targeting RNA demethylases FTO. The imbalance of m6A methylation activates the Wnt signaling pathway by enhancing the WNT7B expression, and thus promoting tumorigenesis and progression of MM. IDH2 might be used as a therapeutic target and a possible prognostic factor for MM. |
doi_str_mv | 10.1038/s41388-021-01939-7 |
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+
cells from MM and its levels appear a progressive increase in the progression of plasma cell dyscrasias. Downregulation of IDH2 increases global m6A RNA levels and reduces myeloma cell growth in vitro, decreases the burden of disease and prolongs overall survival in vivo. IDH2 regulates RNA methylation by activating the RNA demethylase FTO, which is an α-KG-dependent dioxygenase. Furthermore, IDH2-mediated FTO activation decreases the m6A level on WNT7B transcripts, then increases WNT7B expression and thus activated Wnt signaling pathway. Moreover, survival analysis indicates that the elevated expression of IDH2 predicts a poor prognosis. Higher expression of FTO is related to higher International Staging System (ISS) stage and higher Revised-ISS (R-ISS) stage of MM. Collectively, our studies reveal that IDH2 regulates global m6A RNA modification in MM via targeting RNA demethylases FTO. The imbalance of m6A methylation activates the Wnt signaling pathway by enhancing the WNT7B expression, and thus promoting tumorigenesis and progression of MM. IDH2 might be used as a therapeutic target and a possible prognostic factor for MM.</description><identifier>ISSN: 0950-9232</identifier><identifier>ISSN: 1476-5594</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/s41388-021-01939-7</identifier><identifier>PMID: 34274946</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/1 ; 13/109 ; 13/2 ; 13/31 ; 38/77 ; 38/90 ; 59/5 ; 631/67/1990/804 ; 64/60 ; 692/53/2422 ; 82/29 ; Adenosine - analogs & derivatives ; Adenosine - metabolism ; Animals ; Apoptosis ; Cancer ; Carcinogenesis - genetics ; Cell Biology ; Cell Line, Tumor ; Cell survival ; Development and progression ; Dioxygenase ; DNA methylation ; Epigenesis, Genetic ; Epigenetic inheritance ; Epigenetics ; Female ; Gene Expression Regulation, Neoplastic ; Genetic aspects ; Health aspects ; Histones ; Human Genetics ; Humans ; Internal Medicine ; Isocitrate dehydrogenase ; Isocitrate Dehydrogenase - genetics ; Male ; Medical prognosis ; Medicine ; Medicine & Public Health ; Methylation ; Mice ; Monoclonal gammopathy ; Multiple myeloma ; Multiple Myeloma - genetics ; Multiple Myeloma - pathology ; N6-methyladenosine ; Oncology ; Oncology, Experimental ; Oxidoreductases ; Prognosis ; RNA ; RNA Methylation ; RNA modification ; Signal transduction ; Survival analysis ; Tumorigenesis ; Wnt protein</subject><ispartof>Oncogene, 2021-09, Vol.40 (35), p.5393-5402</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited 2021</rights><rights>2021. The Author(s), under exclusive licence to Springer Nature Limited.</rights><rights>COPYRIGHT 2021 Nature Publishing Group</rights><rights>The Author(s), under exclusive licence to Springer Nature Limited 2021.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c442t-43f2316ca73156dfe0377a612ba4b795bcfc8244f9656955dcc872e28ed3c22e3</citedby><cites>FETCH-LOGICAL-c442t-43f2316ca73156dfe0377a612ba4b795bcfc8244f9656955dcc872e28ed3c22e3</cites><orcidid>0000-0002-2732-9354 ; 0000-0002-8552-991X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/34274946$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Song, Sha</creatorcontrib><creatorcontrib>Fan, Gao</creatorcontrib><creatorcontrib>Li, Qi</creatorcontrib><creatorcontrib>Su, Qi</creatorcontrib><creatorcontrib>Zhang, Xinyun</creatorcontrib><creatorcontrib>Xue, Xiaofeng</creatorcontrib><creatorcontrib>Wang, Zhiming</creatorcontrib><creatorcontrib>Qian, Chen’ao</creatorcontrib><creatorcontrib>Jin, Zhou</creatorcontrib><creatorcontrib>Li, Bingzong</creatorcontrib><creatorcontrib>Zhuang, Wenzhuo</creatorcontrib><title>IDH2 contributes to tumorigenesis and poor prognosis by regulating m6A RNA methylation in multiple myeloma</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>Epigenetic alterations have been previously shown to contribute to multiple myeloma (MM) pathogenesis via DNA methylations and histone modifications. RNA methylation, a novel epigenetic modification, is required for cancer cell survival, and targeting this pathway has been proposed as a new therapeutic strategy. The extent to the N6-methyladenosine (m6A)-regulatory pathway functions in MM remains unknown. Here, we show that an imbalance of RNA methylation may underlies the tumorigenesis of MM. Mechanistically, isocitrate dehydrogenase 2 (IDH2) is highly expressed in CD138
+
cells from MM and its levels appear a progressive increase in the progression of plasma cell dyscrasias. Downregulation of IDH2 increases global m6A RNA levels and reduces myeloma cell growth in vitro, decreases the burden of disease and prolongs overall survival in vivo. IDH2 regulates RNA methylation by activating the RNA demethylase FTO, which is an α-KG-dependent dioxygenase. Furthermore, IDH2-mediated FTO activation decreases the m6A level on WNT7B transcripts, then increases WNT7B expression and thus activated Wnt signaling pathway. Moreover, survival analysis indicates that the elevated expression of IDH2 predicts a poor prognosis. Higher expression of FTO is related to higher International Staging System (ISS) stage and higher Revised-ISS (R-ISS) stage of MM. Collectively, our studies reveal that IDH2 regulates global m6A RNA modification in MM via targeting RNA demethylases FTO. The imbalance of m6A methylation activates the Wnt signaling pathway by enhancing the WNT7B expression, and thus promoting tumorigenesis and progression of MM. IDH2 might be used as a therapeutic target and a possible prognostic factor for MM.</description><subject>13/1</subject><subject>13/109</subject><subject>13/2</subject><subject>13/31</subject><subject>38/77</subject><subject>38/90</subject><subject>59/5</subject><subject>631/67/1990/804</subject><subject>64/60</subject><subject>692/53/2422</subject><subject>82/29</subject><subject>Adenosine - analogs & derivatives</subject><subject>Adenosine - metabolism</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Cancer</subject><subject>Carcinogenesis - genetics</subject><subject>Cell Biology</subject><subject>Cell Line, Tumor</subject><subject>Cell survival</subject><subject>Development and progression</subject><subject>Dioxygenase</subject><subject>DNA methylation</subject><subject>Epigenesis, Genetic</subject><subject>Epigenetic inheritance</subject><subject>Epigenetics</subject><subject>Female</subject><subject>Gene Expression Regulation, Neoplastic</subject><subject>Genetic aspects</subject><subject>Health aspects</subject><subject>Histones</subject><subject>Human Genetics</subject><subject>Humans</subject><subject>Internal Medicine</subject><subject>Isocitrate dehydrogenase</subject><subject>Isocitrate Dehydrogenase - genetics</subject><subject>Male</subject><subject>Medical prognosis</subject><subject>Medicine</subject><subject>Medicine & Public Health</subject><subject>Methylation</subject><subject>Mice</subject><subject>Monoclonal gammopathy</subject><subject>Multiple myeloma</subject><subject>Multiple Myeloma - genetics</subject><subject>Multiple Myeloma - pathology</subject><subject>N6-methyladenosine</subject><subject>Oncology</subject><subject>Oncology, Experimental</subject><subject>Oxidoreductases</subject><subject>Prognosis</subject><subject>RNA</subject><subject>RNA Methylation</subject><subject>RNA modification</subject><subject>Signal transduction</subject><subject>Survival analysis</subject><subject>Tumorigenesis</subject><subject>Wnt protein</subject><issn>0950-9232</issn><issn>1476-5594</issn><issn>1476-5594</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><recordid>eNp9kU9rFTEUxQdR7Gv1C7iQgBs3U_M_k-Wj1bZQFETXIZO5M-YxkzyTzOJ9e_N81aKIZBG4-Z3DuTlN84rgS4JZ9y5zwrquxZS0mGimW_Wk2RCuZCuE5k-bDdYCt5oyetac57zDGCuN6fPmjHGquOZy0-zurm8pcjGU5Pu1QEYlorIuMfkJAmSfkQ0D2seY0D7FKcTjqD-gBNM62-LDhBa5RZ8_btEC5dvhOIsB-YCWdS5-PwNaDjDHxb5ono12zvDy4b5ovn54_-Xqtr3_dHN3tb1vHee0tJyNlBHprGJEyGEEzJSyktDe8l5p0bvRdZTzUUshtRCDc52iQDsYmKMU2EXz9uRb835fIRez-Oxgnm2AuGZDhWCUdZKQir75C93FNYWarlKyY5oJLh-pyc5gfBhjSdYdTc1WKl67qEErdfkPqp4BFl8_GEZf538I6EngUsw5wWj2yS82HQzB5liwORVsasHmZ8FGVdHrh8Rrv8DwW_Kr0QqwE5DrU5ggPa70H9sf0qWvCQ</recordid><startdate>20210902</startdate><enddate>20210902</enddate><creator>Song, Sha</creator><creator>Fan, Gao</creator><creator>Li, Qi</creator><creator>Su, Qi</creator><creator>Zhang, Xinyun</creator><creator>Xue, Xiaofeng</creator><creator>Wang, Zhiming</creator><creator>Qian, Chen’ao</creator><creator>Jin, Zhou</creator><creator>Li, Bingzong</creator><creator>Zhuang, Wenzhuo</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>PRINS</scope><scope>Q9U</scope><scope>RC3</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-2732-9354</orcidid><orcidid>https://orcid.org/0000-0002-8552-991X</orcidid></search><sort><creationdate>20210902</creationdate><title>IDH2 contributes to tumorigenesis and poor prognosis by regulating m6A RNA methylation in multiple myeloma</title><author>Song, Sha ; Fan, Gao ; Li, Qi ; Su, Qi ; Zhang, Xinyun ; Xue, Xiaofeng ; Wang, Zhiming ; Qian, Chen’ao ; Jin, Zhou ; Li, Bingzong ; Zhuang, Wenzhuo</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c442t-43f2316ca73156dfe0377a612ba4b795bcfc8244f9656955dcc872e28ed3c22e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>13/1</topic><topic>13/109</topic><topic>13/2</topic><topic>13/31</topic><topic>38/77</topic><topic>38/90</topic><topic>59/5</topic><topic>631/67/1990/804</topic><topic>64/60</topic><topic>692/53/2422</topic><topic>82/29</topic><topic>Adenosine - 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Academic</collection><jtitle>Oncogene</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Song, Sha</au><au>Fan, Gao</au><au>Li, Qi</au><au>Su, Qi</au><au>Zhang, Xinyun</au><au>Xue, Xiaofeng</au><au>Wang, Zhiming</au><au>Qian, Chen’ao</au><au>Jin, Zhou</au><au>Li, Bingzong</au><au>Zhuang, Wenzhuo</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>IDH2 contributes to tumorigenesis and poor prognosis by regulating m6A RNA methylation in multiple myeloma</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><addtitle>Oncogene</addtitle><date>2021-09-02</date><risdate>2021</risdate><volume>40</volume><issue>35</issue><spage>5393</spage><epage>5402</epage><pages>5393-5402</pages><issn>0950-9232</issn><issn>1476-5594</issn><eissn>1476-5594</eissn><abstract>Epigenetic alterations have been previously shown to contribute to multiple myeloma (MM) pathogenesis via DNA methylations and histone modifications. RNA methylation, a novel epigenetic modification, is required for cancer cell survival, and targeting this pathway has been proposed as a new therapeutic strategy. The extent to the N6-methyladenosine (m6A)-regulatory pathway functions in MM remains unknown. Here, we show that an imbalance of RNA methylation may underlies the tumorigenesis of MM. Mechanistically, isocitrate dehydrogenase 2 (IDH2) is highly expressed in CD138
+
cells from MM and its levels appear a progressive increase in the progression of plasma cell dyscrasias. Downregulation of IDH2 increases global m6A RNA levels and reduces myeloma cell growth in vitro, decreases the burden of disease and prolongs overall survival in vivo. IDH2 regulates RNA methylation by activating the RNA demethylase FTO, which is an α-KG-dependent dioxygenase. Furthermore, IDH2-mediated FTO activation decreases the m6A level on WNT7B transcripts, then increases WNT7B expression and thus activated Wnt signaling pathway. Moreover, survival analysis indicates that the elevated expression of IDH2 predicts a poor prognosis. Higher expression of FTO is related to higher International Staging System (ISS) stage and higher Revised-ISS (R-ISS) stage of MM. Collectively, our studies reveal that IDH2 regulates global m6A RNA modification in MM via targeting RNA demethylases FTO. The imbalance of m6A methylation activates the Wnt signaling pathway by enhancing the WNT7B expression, and thus promoting tumorigenesis and progression of MM. IDH2 might be used as a therapeutic target and a possible prognostic factor for MM.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>34274946</pmid><doi>10.1038/s41388-021-01939-7</doi><tpages>10</tpages><orcidid>https://orcid.org/0000-0002-2732-9354</orcidid><orcidid>https://orcid.org/0000-0002-8552-991X</orcidid></addata></record> |
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subjects | 13/1 13/109 13/2 13/31 38/77 38/90 59/5 631/67/1990/804 64/60 692/53/2422 82/29 Adenosine - analogs & derivatives Adenosine - metabolism Animals Apoptosis Cancer Carcinogenesis - genetics Cell Biology Cell Line, Tumor Cell survival Development and progression Dioxygenase DNA methylation Epigenesis, Genetic Epigenetic inheritance Epigenetics Female Gene Expression Regulation, Neoplastic Genetic aspects Health aspects Histones Human Genetics Humans Internal Medicine Isocitrate dehydrogenase Isocitrate Dehydrogenase - genetics Male Medical prognosis Medicine Medicine & Public Health Methylation Mice Monoclonal gammopathy Multiple myeloma Multiple Myeloma - genetics Multiple Myeloma - pathology N6-methyladenosine Oncology Oncology, Experimental Oxidoreductases Prognosis RNA RNA Methylation RNA modification Signal transduction Survival analysis Tumorigenesis Wnt protein |
title | IDH2 contributes to tumorigenesis and poor prognosis by regulating m6A RNA methylation in multiple myeloma |
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