Inflammation-induced JMJD2D promotes colitis recovery and colon tumorigenesis by activating Hedgehog signaling
Histone demethylase JMJD2D can promote gene expression by specifically demethylating H3K9me2/3. The role of JMJD2D in colitis and colitis-associated colorectal cancer (CRC) progression remains unclear. Here, we show that colonic JMJD2D is induced by TNFα during dextran sulfate sodium-induced colitis...
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| Veröffentlicht in: | Oncogene 2020-04, Vol.39 (16), p.3336-3353 |
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| creator | Zhuo, Minghui Chen, Wenbo Shang, Shaohui Guo, Peng Peng, Kesong Li, Ming Mo, Pingli Zhang, Yongyou Qiu, Xingfeng Li, Wengang Yu, Chundong |
| description | Histone demethylase JMJD2D can promote gene expression by specifically demethylating H3K9me2/3. The role of JMJD2D in colitis and colitis-associated colorectal cancer (CRC) progression remains unclear. Here, we show that colonic JMJD2D is induced by TNFα during dextran sulfate sodium-induced colitis. JMJD2D-deficient mice exhibit more severe colon damage and defective colon regeneration due to impaired Hedgehog signaling activation after colitis. JMJD2D knockdown in CRC cells suppresses Hedgehog signaling, resulting in reduced CRC growth and metastasis. Mechanistically, JMJD2D promotes Hedgehog target gene expression through interacting with Gli2 to reduce H3K9me3 levels at the promoter. Clinically, JMJD2D expression is upregulated and positively correlated with Gli2 expression in human inflammatory bowel disease specimens and CRC specimens. The JMJD2D inhibitor 5-c-8HQ or aspirin synergizes with Hedgehog inhibitor vismodegib to inhibit CRC cell proliferation and tumorigenesis. Collectively, our findings unveil an essential role of JMJD2D in activating the processes of colonic protection, regeneration, and tumorigenesis. |
| doi_str_mv | 10.1038/s41388-020-1219-2 |
| format | Article |
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The role of JMJD2D in colitis and colitis-associated colorectal cancer (CRC) progression remains unclear. Here, we show that colonic JMJD2D is induced by TNFα during dextran sulfate sodium-induced colitis. JMJD2D-deficient mice exhibit more severe colon damage and defective colon regeneration due to impaired Hedgehog signaling activation after colitis. JMJD2D knockdown in CRC cells suppresses Hedgehog signaling, resulting in reduced CRC growth and metastasis. Mechanistically, JMJD2D promotes Hedgehog target gene expression through interacting with Gli2 to reduce H3K9me3 levels at the promoter. Clinically, JMJD2D expression is upregulated and positively correlated with Gli2 expression in human inflammatory bowel disease specimens and CRC specimens. The JMJD2D inhibitor 5-c-8HQ or aspirin synergizes with Hedgehog inhibitor vismodegib to inhibit CRC cell proliferation and tumorigenesis. Collectively, our findings unveil an essential role of JMJD2D in activating the processes of colonic protection, regeneration, and tumorigenesis.</description><identifier>ISSN: 0950-9232</identifier><identifier>EISSN: 1476-5594</identifier><identifier>DOI: 10.1038/s41388-020-1219-2</identifier><identifier>PMID: 32094404</identifier><language>eng</language><publisher>London: Nature Publishing Group UK</publisher><subject>13/1 ; 13/2 ; 13/51 ; 13/89 ; 45/15 ; 631/250/256 ; 631/67/1504/1885 ; 64/60 ; 82/83 ; 96/106 ; Anilides - pharmacology ; Animals ; Apoptosis ; Aspirin ; Aspirin - pharmacology ; Carcinogenesis - drug effects ; Care and treatment ; Cell Biology ; Cell proliferation ; Cell Proliferation - drug effects ; Cellular signal transduction ; Colitis ; Colitis - drug therapy ; Colitis - genetics ; Colitis - pathology ; Colon ; Colorectal cancer ; Colorectal carcinoma ; Colorectal Neoplasms - drug therapy ; Colorectal Neoplasms - genetics ; Colorectal Neoplasms - pathology ; Complications and side effects ; Development and progression ; Dextran ; Dextran sulfate ; Disease Models, Animal ; Drug Synergism ; Gene expression ; Gene Expression Regulation, Neoplastic - drug effects ; Gene Knockdown Techniques ; Genetic aspects ; Health aspects ; Hedgehog protein ; Hedgehog proteins ; Hedgehog Proteins - antagonists & inhibitors ; Hedgehog Proteins - genetics ; Histones ; Human Genetics ; Humans ; Inflammation - drug therapy ; Inflammation - genetics ; Inflammation - pathology ; Inflammatory bowel disease ; Inflammatory bowel diseases ; Internal Medicine ; Intestine ; Jumonji Domain-Containing Histone Demethylases - antagonists & inhibitors ; Jumonji Domain-Containing Histone Demethylases - genetics ; Medicine ; Medicine & Public Health ; Metastases ; Mice ; Oncology ; Pyridines - pharmacology ; Signal Transduction - drug effects ; Signal Transduction - genetics ; Tumor necrosis factor ; Tumor necrosis factor-α ; Tumorigenesis</subject><ispartof>Oncogene, 2020-04, Vol.39 (16), p.3336-3353</ispartof><rights>The Author(s), under exclusive licence to Springer Nature Limited 2020</rights><rights>COPYRIGHT 2020 Nature Publishing Group</rights><rights>The Author(s), under exclusive licence to Springer Nature Limited 2020.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c533t-166aa210e84d82a73c246b5757bd17b2c4c05ecf9376dc461834ddbb7907c3683</citedby><cites>FETCH-LOGICAL-c533t-166aa210e84d82a73c246b5757bd17b2c4c05ecf9376dc461834ddbb7907c3683</cites><orcidid>0000-0002-4141-8345</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/s41388-020-1219-2$$EPDF$$P50$$Gspringer$$H</linktopdf><linktohtml>$$Uhttps://link.springer.com/10.1038/s41388-020-1219-2$$EHTML$$P50$$Gspringer$$H</linktohtml><link.rule.ids>314,780,784,27924,27925,41488,42557,51319</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32094404$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zhuo, Minghui</creatorcontrib><creatorcontrib>Chen, Wenbo</creatorcontrib><creatorcontrib>Shang, Shaohui</creatorcontrib><creatorcontrib>Guo, Peng</creatorcontrib><creatorcontrib>Peng, Kesong</creatorcontrib><creatorcontrib>Li, Ming</creatorcontrib><creatorcontrib>Mo, Pingli</creatorcontrib><creatorcontrib>Zhang, Yongyou</creatorcontrib><creatorcontrib>Qiu, Xingfeng</creatorcontrib><creatorcontrib>Li, Wengang</creatorcontrib><creatorcontrib>Yu, Chundong</creatorcontrib><title>Inflammation-induced JMJD2D promotes colitis recovery and colon tumorigenesis by activating Hedgehog signaling</title><title>Oncogene</title><addtitle>Oncogene</addtitle><addtitle>Oncogene</addtitle><description>Histone demethylase JMJD2D can promote gene expression by specifically demethylating H3K9me2/3. The role of JMJD2D in colitis and colitis-associated colorectal cancer (CRC) progression remains unclear. Here, we show that colonic JMJD2D is induced by TNFα during dextran sulfate sodium-induced colitis. JMJD2D-deficient mice exhibit more severe colon damage and defective colon regeneration due to impaired Hedgehog signaling activation after colitis. JMJD2D knockdown in CRC cells suppresses Hedgehog signaling, resulting in reduced CRC growth and metastasis. Mechanistically, JMJD2D promotes Hedgehog target gene expression through interacting with Gli2 to reduce H3K9me3 levels at the promoter. Clinically, JMJD2D expression is upregulated and positively correlated with Gli2 expression in human inflammatory bowel disease specimens and CRC specimens. The JMJD2D inhibitor 5-c-8HQ or aspirin synergizes with Hedgehog inhibitor vismodegib to inhibit CRC cell proliferation and tumorigenesis. Collectively, our findings unveil an essential role of JMJD2D in activating the processes of colonic protection, regeneration, and tumorigenesis.</description><subject>13/1</subject><subject>13/2</subject><subject>13/51</subject><subject>13/89</subject><subject>45/15</subject><subject>631/250/256</subject><subject>631/67/1504/1885</subject><subject>64/60</subject><subject>82/83</subject><subject>96/106</subject><subject>Anilides - pharmacology</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Aspirin</subject><subject>Aspirin - pharmacology</subject><subject>Carcinogenesis - drug effects</subject><subject>Care and treatment</subject><subject>Cell Biology</subject><subject>Cell proliferation</subject><subject>Cell Proliferation - drug effects</subject><subject>Cellular signal transduction</subject><subject>Colitis</subject><subject>Colitis - drug therapy</subject><subject>Colitis - genetics</subject><subject>Colitis - 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Hedgehog signaling</atitle><jtitle>Oncogene</jtitle><stitle>Oncogene</stitle><addtitle>Oncogene</addtitle><date>2020-04-16</date><risdate>2020</risdate><volume>39</volume><issue>16</issue><spage>3336</spage><epage>3353</epage><pages>3336-3353</pages><issn>0950-9232</issn><eissn>1476-5594</eissn><abstract>Histone demethylase JMJD2D can promote gene expression by specifically demethylating H3K9me2/3. The role of JMJD2D in colitis and colitis-associated colorectal cancer (CRC) progression remains unclear. Here, we show that colonic JMJD2D is induced by TNFα during dextran sulfate sodium-induced colitis. JMJD2D-deficient mice exhibit more severe colon damage and defective colon regeneration due to impaired Hedgehog signaling activation after colitis. JMJD2D knockdown in CRC cells suppresses Hedgehog signaling, resulting in reduced CRC growth and metastasis. Mechanistically, JMJD2D promotes Hedgehog target gene expression through interacting with Gli2 to reduce H3K9me3 levels at the promoter. Clinically, JMJD2D expression is upregulated and positively correlated with Gli2 expression in human inflammatory bowel disease specimens and CRC specimens. The JMJD2D inhibitor 5-c-8HQ or aspirin synergizes with Hedgehog inhibitor vismodegib to inhibit CRC cell proliferation and tumorigenesis. Collectively, our findings unveil an essential role of JMJD2D in activating the processes of colonic protection, regeneration, and tumorigenesis.</abstract><cop>London</cop><pub>Nature Publishing Group UK</pub><pmid>32094404</pmid><doi>10.1038/s41388-020-1219-2</doi><tpages>18</tpages><orcidid>https://orcid.org/0000-0002-4141-8345</orcidid></addata></record> |
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| subjects | 13/1 13/2 13/51 13/89 45/15 631/250/256 631/67/1504/1885 64/60 82/83 96/106 Anilides - pharmacology Animals Apoptosis Aspirin Aspirin - pharmacology Carcinogenesis - drug effects Care and treatment Cell Biology Cell proliferation Cell Proliferation - drug effects Cellular signal transduction Colitis Colitis - drug therapy Colitis - genetics Colitis - pathology Colon Colorectal cancer Colorectal carcinoma Colorectal Neoplasms - drug therapy Colorectal Neoplasms - genetics Colorectal Neoplasms - pathology Complications and side effects Development and progression Dextran Dextran sulfate Disease Models, Animal Drug Synergism Gene expression Gene Expression Regulation, Neoplastic - drug effects Gene Knockdown Techniques Genetic aspects Health aspects Hedgehog protein Hedgehog proteins Hedgehog Proteins - antagonists & inhibitors Hedgehog Proteins - genetics Histones Human Genetics Humans Inflammation - drug therapy Inflammation - genetics Inflammation - pathology Inflammatory bowel disease Inflammatory bowel diseases Internal Medicine Intestine Jumonji Domain-Containing Histone Demethylases - antagonists & inhibitors Jumonji Domain-Containing Histone Demethylases - genetics Medicine Medicine & Public Health Metastases Mice Oncology Pyridines - pharmacology Signal Transduction - drug effects Signal Transduction - genetics Tumor necrosis factor Tumor necrosis factor-α Tumorigenesis |
| title | Inflammation-induced JMJD2D promotes colitis recovery and colon tumorigenesis by activating Hedgehog signaling |
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