S-Adenosyl-L-methionine-competitive inhibitors of the histone methyltransferase EZH2 induce autophagy and enhance drug sensitivity in cancer cells
The enhancer of zeste homolog 2 (EZH2) has emerged as a novel anticancer target. Various EZH2 inhibitors have been developed in recent years. Among these, 3-deazaneplanocin A (DZNep) is known to deplete EZH2 protein expression through an indirect pathway. In contrast, GSK343 directly inhibits enzyme...
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| Veröffentlicht in: | Anti-cancer drugs 2015-02, Vol.26 (2), p.139-147 |
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| creator | Liu, Tsang-Pai Lo, Hsiang-Ling Wei, Li-Shan Hao-yun Hsiao, Heidi Yang, Pei-Ming |
| description | The enhancer of zeste homolog 2 (EZH2) has emerged as a novel anticancer target. Various EZH2 inhibitors have been developed in recent years. Among these, 3-deazaneplanocin A (DZNep) is known to deplete EZH2 protein expression through an indirect pathway. In contrast, GSK343 directly inhibits enzyme activity through an S-adenosyl-L-methionine-competitive pathway. Therefore, we proposed that DZNep and GSK343 may exert differential effects against cancer cells. In this study, we found that GSK343 but not DZNep induced autophagic cell death of cancer cells. Inhibition of EZH2 expression was not required for GSK343-induced autophagy. In addition, GSK343 enhanced the anticancer activity of a multikinase inhibitor, sorafenib, in human hepatocellular carcinoma cells. Our results show that GSK343 is a more potent anticancer agent than DZNep, and for the first time, we show that it acts as an autophagy inducer. |
| doi_str_mv | 10.1097/CAD.0000000000000166 |
| format | Article |
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Various EZH2 inhibitors have been developed in recent years. Among these, 3-deazaneplanocin A (DZNep) is known to deplete EZH2 protein expression through an indirect pathway. In contrast, GSK343 directly inhibits enzyme activity through an S-adenosyl-L-methionine-competitive pathway. Therefore, we proposed that DZNep and GSK343 may exert differential effects against cancer cells. In this study, we found that GSK343 but not DZNep induced autophagic cell death of cancer cells. Inhibition of EZH2 expression was not required for GSK343-induced autophagy. In addition, GSK343 enhanced the anticancer activity of a multikinase inhibitor, sorafenib, in human hepatocellular carcinoma cells. Our results show that GSK343 is a more potent anticancer agent than DZNep, and for the first time, we show that it acts as an autophagy inducer.</description><identifier>ISSN: 0959-4973</identifier><identifier>EISSN: 1473-5741</identifier><identifier>DOI: 10.1097/CAD.0000000000000166</identifier><identifier>PMID: 25203626</identifier><language>eng</language><publisher>England: Wolters Kluwer Health | Lippincott Williams & Wilkins</publisher><subject><![CDATA[Adenosine - administration & dosage ; Adenosine - analogs & derivatives ; Adenosine - pharmacology ; Antineoplastic Combined Chemotherapy Protocols - pharmacology ; Autophagy - drug effects ; Cell Line, Tumor - drug effects ; Cell Survival - drug effects ; Enhancer of Zeste Homolog 2 Protein ; Enzyme Inhibitors - metabolism ; Enzyme Inhibitors - pharmacology ; Gene Knockdown Techniques ; Hep G2 Cells - drug effects ; Histone-Lysine N-Methyltransferase - antagonists & inhibitors ; Humans ; Indazoles - administration & dosage ; Indazoles - pharmacology ; Niacinamide - administration & dosage ; Niacinamide - analogs & derivatives ; Niacinamide - pharmacology ; Phenylurea Compounds - administration & dosage ; Phenylurea Compounds - pharmacology ; Polycomb Repressive Complex 2 - antagonists & inhibitors ; Polycomb Repressive Complex 2 - genetics ; Polycomb Repressive Complex 2 - metabolism ; Preclinical Reports ; Pyridones - administration & dosage ; Pyridones - pharmacology ; S-Adenosylmethionine - metabolism]]></subject><ispartof>Anti-cancer drugs, 2015-02, Vol.26 (2), p.139-147</ispartof><rights>2015 Wolters Kluwer Health | Lippincott Williams & Wilkins</rights><rights>2015 Wolters Kluwer Health | Lippincott Williams & Wilkins 2015</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5416-493c40e4413c3914ff1eefa86f2bc2466d9154aedfb73ca089ca7dadc43b05983</citedby><cites>FETCH-LOGICAL-c5416-493c40e4413c3914ff1eefa86f2bc2466d9154aedfb73ca089ca7dadc43b05983</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,778,782,883,27907,27908</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25203626$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liu, Tsang-Pai</creatorcontrib><creatorcontrib>Lo, Hsiang-Ling</creatorcontrib><creatorcontrib>Wei, Li-Shan</creatorcontrib><creatorcontrib>Hao-yun Hsiao, Heidi</creatorcontrib><creatorcontrib>Yang, Pei-Ming</creatorcontrib><title>S-Adenosyl-L-methionine-competitive inhibitors of the histone methyltransferase EZH2 induce autophagy and enhance drug sensitivity in cancer cells</title><title>Anti-cancer drugs</title><addtitle>Anticancer Drugs</addtitle><description>The enhancer of zeste homolog 2 (EZH2) has emerged as a novel anticancer target. Various EZH2 inhibitors have been developed in recent years. Among these, 3-deazaneplanocin A (DZNep) is known to deplete EZH2 protein expression through an indirect pathway. In contrast, GSK343 directly inhibits enzyme activity through an S-adenosyl-L-methionine-competitive pathway. Therefore, we proposed that DZNep and GSK343 may exert differential effects against cancer cells. In this study, we found that GSK343 but not DZNep induced autophagic cell death of cancer cells. Inhibition of EZH2 expression was not required for GSK343-induced autophagy. In addition, GSK343 enhanced the anticancer activity of a multikinase inhibitor, sorafenib, in human hepatocellular carcinoma cells. Our results show that GSK343 is a more potent anticancer agent than DZNep, and for the first time, we show that it acts as an autophagy inducer.</description><subject>Adenosine - administration & dosage</subject><subject>Adenosine - analogs & derivatives</subject><subject>Adenosine - pharmacology</subject><subject>Antineoplastic Combined Chemotherapy Protocols - pharmacology</subject><subject>Autophagy - drug effects</subject><subject>Cell Line, Tumor - drug effects</subject><subject>Cell Survival - drug effects</subject><subject>Enhancer of Zeste Homolog 2 Protein</subject><subject>Enzyme Inhibitors - metabolism</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Gene Knockdown Techniques</subject><subject>Hep G2 Cells - drug effects</subject><subject>Histone-Lysine N-Methyltransferase - antagonists & inhibitors</subject><subject>Humans</subject><subject>Indazoles - administration & dosage</subject><subject>Indazoles - pharmacology</subject><subject>Niacinamide - administration & dosage</subject><subject>Niacinamide - analogs & derivatives</subject><subject>Niacinamide - pharmacology</subject><subject>Phenylurea Compounds - administration & dosage</subject><subject>Phenylurea Compounds - pharmacology</subject><subject>Polycomb Repressive Complex 2 - antagonists & inhibitors</subject><subject>Polycomb Repressive Complex 2 - genetics</subject><subject>Polycomb Repressive Complex 2 - metabolism</subject><subject>Preclinical Reports</subject><subject>Pyridones - administration & dosage</subject><subject>Pyridones - pharmacology</subject><subject>S-Adenosylmethionine - metabolism</subject><issn>0959-4973</issn><issn>1473-5741</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkcFu1DAURS1ERYfCHyDkJZsUO3bi8QZpNC0t0kgsChs2luO8TAyJPdhOq_wGX1xHU6rCAuGNpffOvXpXF6E3lJxTIsX77ebinDx9tK6foRXlghWV4PQ5WhFZyYJLwU7Ryxi_ZybP2Qt0WlYlYXVZr9Cvm2LTgvNxHopdMULqrXfWQWH8eIBkk70FbF1vG5t8iNh3OPWAexuTd4AXwTykoF3sIOgI-PLbdZkF7WQA6yn5Q6_3M9auxeB67fK0DdMeR3BxMbdpzjQ2yyZgA8MQX6GTTg8RXj_8Z-jrx8sv2-ti9_nq03azK0zFaZ1zMcMJ8JzIMEl511GATq_rrmxMyeu6lbTiGtquEcxospZGi1a3hrOGVHLNztCHo-9hakZoDbicY1CHYEcdZuW1VX9unO3V3t8qXoq6EjQbvHswCP7nBDGp0cYlgnbgp6hyIYQTLoT4D5TJHEhInlF-RE3wMQboHi-iRC3Nq9y8-rv5LHv7NM2j6HfVGVgfgTs_JAjxxzDdQVA96CH1__a-B7ZLvn0</recordid><startdate>201502</startdate><enddate>201502</enddate><creator>Liu, Tsang-Pai</creator><creator>Lo, Hsiang-Ling</creator><creator>Wei, Li-Shan</creator><creator>Hao-yun Hsiao, Heidi</creator><creator>Yang, Pei-Ming</creator><general>Wolters Kluwer Health | Lippincott Williams & Wilkins</general><general>Lippincott Williams & Wilkins</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>7TO</scope><scope>H94</scope><scope>5PM</scope></search><sort><creationdate>201502</creationdate><title>S-Adenosyl-L-methionine-competitive inhibitors of the histone methyltransferase EZH2 induce autophagy and enhance drug sensitivity in cancer cells</title><author>Liu, Tsang-Pai ; Lo, Hsiang-Ling ; Wei, Li-Shan ; Hao-yun Hsiao, Heidi ; Yang, Pei-Ming</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5416-493c40e4413c3914ff1eefa86f2bc2466d9154aedfb73ca089ca7dadc43b05983</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Adenosine - administration & dosage</topic><topic>Adenosine - analogs & derivatives</topic><topic>Adenosine - pharmacology</topic><topic>Antineoplastic Combined Chemotherapy Protocols - pharmacology</topic><topic>Autophagy - drug effects</topic><topic>Cell Line, Tumor - drug effects</topic><topic>Cell Survival - drug effects</topic><topic>Enhancer of Zeste Homolog 2 Protein</topic><topic>Enzyme Inhibitors - metabolism</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Gene Knockdown Techniques</topic><topic>Hep G2 Cells - drug effects</topic><topic>Histone-Lysine N-Methyltransferase - antagonists & inhibitors</topic><topic>Humans</topic><topic>Indazoles - administration & dosage</topic><topic>Indazoles - pharmacology</topic><topic>Niacinamide - administration & dosage</topic><topic>Niacinamide - analogs & derivatives</topic><topic>Niacinamide - pharmacology</topic><topic>Phenylurea Compounds - administration & dosage</topic><topic>Phenylurea Compounds - pharmacology</topic><topic>Polycomb Repressive Complex 2 - antagonists & inhibitors</topic><topic>Polycomb Repressive Complex 2 - genetics</topic><topic>Polycomb Repressive Complex 2 - metabolism</topic><topic>Preclinical Reports</topic><topic>Pyridones - administration & dosage</topic><topic>Pyridones - pharmacology</topic><topic>S-Adenosylmethionine - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Liu, Tsang-Pai</creatorcontrib><creatorcontrib>Lo, Hsiang-Ling</creatorcontrib><creatorcontrib>Wei, Li-Shan</creatorcontrib><creatorcontrib>Hao-yun Hsiao, Heidi</creatorcontrib><creatorcontrib>Yang, Pei-Ming</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>Oncogenes and Growth Factors Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Anti-cancer drugs</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Liu, Tsang-Pai</au><au>Lo, Hsiang-Ling</au><au>Wei, Li-Shan</au><au>Hao-yun Hsiao, Heidi</au><au>Yang, Pei-Ming</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>S-Adenosyl-L-methionine-competitive inhibitors of the histone methyltransferase EZH2 induce autophagy and enhance drug sensitivity in cancer cells</atitle><jtitle>Anti-cancer drugs</jtitle><addtitle>Anticancer Drugs</addtitle><date>2015-02</date><risdate>2015</risdate><volume>26</volume><issue>2</issue><spage>139</spage><epage>147</epage><pages>139-147</pages><issn>0959-4973</issn><eissn>1473-5741</eissn><abstract>The enhancer of zeste homolog 2 (EZH2) has emerged as a novel anticancer target. Various EZH2 inhibitors have been developed in recent years. Among these, 3-deazaneplanocin A (DZNep) is known to deplete EZH2 protein expression through an indirect pathway. In contrast, GSK343 directly inhibits enzyme activity through an S-adenosyl-L-methionine-competitive pathway. Therefore, we proposed that DZNep and GSK343 may exert differential effects against cancer cells. In this study, we found that GSK343 but not DZNep induced autophagic cell death of cancer cells. Inhibition of EZH2 expression was not required for GSK343-induced autophagy. In addition, GSK343 enhanced the anticancer activity of a multikinase inhibitor, sorafenib, in human hepatocellular carcinoma cells. Our results show that GSK343 is a more potent anticancer agent than DZNep, and for the first time, we show that it acts as an autophagy inducer.</abstract><cop>England</cop><pub>Wolters Kluwer Health | Lippincott Williams & Wilkins</pub><pmid>25203626</pmid><doi>10.1097/CAD.0000000000000166</doi><tpages>9</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adenosine - administration & dosage Adenosine - analogs & derivatives Adenosine - pharmacology Antineoplastic Combined Chemotherapy Protocols - pharmacology Autophagy - drug effects Cell Line, Tumor - drug effects Cell Survival - drug effects Enhancer of Zeste Homolog 2 Protein Enzyme Inhibitors - metabolism Enzyme Inhibitors - pharmacology Gene Knockdown Techniques Hep G2 Cells - drug effects Histone-Lysine N-Methyltransferase - antagonists & inhibitors Humans Indazoles - administration & dosage Indazoles - pharmacology Niacinamide - administration & dosage Niacinamide - analogs & derivatives Niacinamide - pharmacology Phenylurea Compounds - administration & dosage Phenylurea Compounds - pharmacology Polycomb Repressive Complex 2 - antagonists & inhibitors Polycomb Repressive Complex 2 - genetics Polycomb Repressive Complex 2 - metabolism Preclinical Reports Pyridones - administration & dosage Pyridones - pharmacology S-Adenosylmethionine - metabolism |
| title | S-Adenosyl-L-methionine-competitive inhibitors of the histone methyltransferase EZH2 induce autophagy and enhance drug sensitivity in cancer cells |
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