EZH2 functional dichotomy in reactive oxygen species-stratified glioblastoma
EZH2, well-known for its canonical methyltransferase activity in transcriptional repression in many cancers including glioblastoma (GBM), has an understudied non-canonical function critical for sustained tumor growth. Recent GBM consortial efforts reveal complex molecular heterogeneity for which the...
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creator | Koh, Lynnette Wei Hsien Pang, Qing You Novera, Wisna Lim, See Wee Chong, Yuk Kien Liu, Jinyue Ang, Samantha Ya Lyn Loh, Ron Weng Yee Shao, Huilin Ching, Jianhong Wang, Yulan Yip, Stephen Tan, Patrick Li, Shang Low, David Chyi Yeu Phelan, Anne Rosser, Gabriel Tan, Nguan Soon Tang, Carol Ang, Beng Ti |
description | EZH2, well-known for its canonical methyltransferase activity in transcriptional repression in many cancers including glioblastoma (GBM), has an understudied non-canonical function critical for sustained tumor growth. Recent GBM consortial efforts reveal complex molecular heterogeneity for which therapeutic vulnerabilities correlated with subtype stratification remain relatively unexplored. Current enzymatic EZH2 inhibitors (EZH2inh) targeting its canonical SET domain show limited efficacy and lack durable response, suggesting that underlying differences in the non-canonical pathway may yield new knowledge. Here, we unveiled dual roles of the EZH2 CXC domain in therapeutically-distinct, reactive oxygen species (ROS)-stratified tumors.
We analyzed differentially expressed genes between ROS classes by examining cis-regulatory elements as well as clustering of activities and pathways to identify EZH2 as the key mediator in ROS-stratified cohorts. Pull-down assays and CRISPR knockout of EZH2 domains were used to dissect the distinct functions of EZH2 in ROS-stratified GBM cells. The efficacy of NF-κB-inducing kinase inhibitor (NIKinh) and standard-of-care temozolomide was evaluated using orthotopic patient-derived GBM xenografts.
In ROS(+) tumors, CXC-mediated co-interaction with RelB drives constitutive activation of non-canonical NF-κB2 signaling, sustaining the ROS(+) chemoresistant phenotype. In contrast, in ROS(-) subtypes, PRC2 methyltransferase activity represses canonical NF-κB. Addressing the lack of EZH2inh targeting its non-methyltransferase roles, we utilized a brain-penetrant NIKinh that disrupts EZH2-RelB binding, consequently prolonging survival in orthotopic ROS(+)-implanted mice.
Our findings highlight the functional dichotomy of the EZH2 CXC domain in governing ROS-stratified therapeutic resistance, thereby advocating for the development of therapeutic approaches targeting its non-canonical activities and underscoring the significance of patient stratification methodologies. |
doi_str_mv | 10.1093/neuonc/noae206 |
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We analyzed differentially expressed genes between ROS classes by examining cis-regulatory elements as well as clustering of activities and pathways to identify EZH2 as the key mediator in ROS-stratified cohorts. Pull-down assays and CRISPR knockout of EZH2 domains were used to dissect the distinct functions of EZH2 in ROS-stratified GBM cells. The efficacy of NF-κB-inducing kinase inhibitor (NIKinh) and standard-of-care temozolomide was evaluated using orthotopic patient-derived GBM xenografts.
In ROS(+) tumors, CXC-mediated co-interaction with RelB drives constitutive activation of non-canonical NF-κB2 signaling, sustaining the ROS(+) chemoresistant phenotype. In contrast, in ROS(-) subtypes, PRC2 methyltransferase activity represses canonical NF-κB. Addressing the lack of EZH2inh targeting its non-methyltransferase roles, we utilized a brain-penetrant NIKinh that disrupts EZH2-RelB binding, consequently prolonging survival in orthotopic ROS(+)-implanted mice.
Our findings highlight the functional dichotomy of the EZH2 CXC domain in governing ROS-stratified therapeutic resistance, thereby advocating for the development of therapeutic approaches targeting its non-canonical activities and underscoring the significance of patient stratification methodologies.</description><identifier>ISSN: 1522-8517</identifier><identifier>ISSN: 1523-5866</identifier><identifier>EISSN: 1523-5866</identifier><identifier>DOI: 10.1093/neuonc/noae206</identifier><identifier>PMID: 39373211</identifier><language>eng</language><publisher>England</publisher><ispartof>Neuro-oncology (Charlottesville, Va.), 2024-10</ispartof><rights>The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c180t-d79961e47a7584df74919b4cd858d8211eb33050f9cc10eb964e9317dedc25163</cites><orcidid>0000-0002-1835-5083 ; 0000-0002-8514-9861 ; 0000-0003-0136-7341</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27903,27904</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39373211$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Koh, Lynnette Wei Hsien</creatorcontrib><creatorcontrib>Pang, Qing You</creatorcontrib><creatorcontrib>Novera, Wisna</creatorcontrib><creatorcontrib>Lim, See Wee</creatorcontrib><creatorcontrib>Chong, Yuk Kien</creatorcontrib><creatorcontrib>Liu, Jinyue</creatorcontrib><creatorcontrib>Ang, Samantha Ya Lyn</creatorcontrib><creatorcontrib>Loh, Ron Weng Yee</creatorcontrib><creatorcontrib>Shao, Huilin</creatorcontrib><creatorcontrib>Ching, Jianhong</creatorcontrib><creatorcontrib>Wang, Yulan</creatorcontrib><creatorcontrib>Yip, Stephen</creatorcontrib><creatorcontrib>Tan, Patrick</creatorcontrib><creatorcontrib>Li, Shang</creatorcontrib><creatorcontrib>Low, David Chyi Yeu</creatorcontrib><creatorcontrib>Phelan, Anne</creatorcontrib><creatorcontrib>Rosser, Gabriel</creatorcontrib><creatorcontrib>Tan, Nguan Soon</creatorcontrib><creatorcontrib>Tang, Carol</creatorcontrib><creatorcontrib>Ang, Beng Ti</creatorcontrib><title>EZH2 functional dichotomy in reactive oxygen species-stratified glioblastoma</title><title>Neuro-oncology (Charlottesville, Va.)</title><addtitle>Neuro Oncol</addtitle><description>EZH2, well-known for its canonical methyltransferase activity in transcriptional repression in many cancers including glioblastoma (GBM), has an understudied non-canonical function critical for sustained tumor growth. Recent GBM consortial efforts reveal complex molecular heterogeneity for which therapeutic vulnerabilities correlated with subtype stratification remain relatively unexplored. Current enzymatic EZH2 inhibitors (EZH2inh) targeting its canonical SET domain show limited efficacy and lack durable response, suggesting that underlying differences in the non-canonical pathway may yield new knowledge. Here, we unveiled dual roles of the EZH2 CXC domain in therapeutically-distinct, reactive oxygen species (ROS)-stratified tumors.
We analyzed differentially expressed genes between ROS classes by examining cis-regulatory elements as well as clustering of activities and pathways to identify EZH2 as the key mediator in ROS-stratified cohorts. Pull-down assays and CRISPR knockout of EZH2 domains were used to dissect the distinct functions of EZH2 in ROS-stratified GBM cells. The efficacy of NF-κB-inducing kinase inhibitor (NIKinh) and standard-of-care temozolomide was evaluated using orthotopic patient-derived GBM xenografts.
In ROS(+) tumors, CXC-mediated co-interaction with RelB drives constitutive activation of non-canonical NF-κB2 signaling, sustaining the ROS(+) chemoresistant phenotype. In contrast, in ROS(-) subtypes, PRC2 methyltransferase activity represses canonical NF-κB. Addressing the lack of EZH2inh targeting its non-methyltransferase roles, we utilized a brain-penetrant NIKinh that disrupts EZH2-RelB binding, consequently prolonging survival in orthotopic ROS(+)-implanted mice.
Our findings highlight the functional dichotomy of the EZH2 CXC domain in governing ROS-stratified therapeutic resistance, thereby advocating for the development of therapeutic approaches targeting its non-canonical activities and underscoring the significance of patient stratification methodologies.</description><issn>1522-8517</issn><issn>1523-5866</issn><issn>1523-5866</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><recordid>eNo9kDFPwzAQRi0EoqWwMqKMLGl9dhzHI6oKRarEAgtL5NiXYpTYJU4Q_fcEWpjudHrfp9Mj5BroHKjiC49D8Gbhg0ZG8xMyBcF4Koo8P_3dWVoIkBNyEeM7pQxEDudkwhWXnAFMyWb1umZJPXjTu-B1k1hn3kIf2n3ifNKhHu-fmISv_RZ9EndoHMY09p3uXe3QJtvGharRcYzoS3JW6ybi1XHOyMv96nm5TjdPD4_Lu01qoKB9aqVSOWAmtRRFZmuZKVBVZmwhCluMb2HFORW0VsYAxUrlGSoO0qI1TEDOZ-T20LvrwseAsS9bFw02jfYYhlhyAC4FU1yM6PyAmi7E2GFd7jrX6m5fAi1_DJYHg-XR4Bi4OXYPVYv2H_9Txr8BNxNvCw</recordid><startdate>20241007</startdate><enddate>20241007</enddate><creator>Koh, Lynnette Wei Hsien</creator><creator>Pang, Qing You</creator><creator>Novera, Wisna</creator><creator>Lim, See Wee</creator><creator>Chong, Yuk Kien</creator><creator>Liu, Jinyue</creator><creator>Ang, Samantha Ya Lyn</creator><creator>Loh, Ron Weng Yee</creator><creator>Shao, Huilin</creator><creator>Ching, Jianhong</creator><creator>Wang, Yulan</creator><creator>Yip, Stephen</creator><creator>Tan, Patrick</creator><creator>Li, Shang</creator><creator>Low, David Chyi Yeu</creator><creator>Phelan, Anne</creator><creator>Rosser, Gabriel</creator><creator>Tan, Nguan Soon</creator><creator>Tang, Carol</creator><creator>Ang, Beng Ti</creator><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0002-1835-5083</orcidid><orcidid>https://orcid.org/0000-0002-8514-9861</orcidid><orcidid>https://orcid.org/0000-0003-0136-7341</orcidid></search><sort><creationdate>20241007</creationdate><title>EZH2 functional dichotomy in reactive oxygen species-stratified glioblastoma</title><author>Koh, Lynnette Wei Hsien ; Pang, Qing You ; Novera, Wisna ; Lim, See Wee ; Chong, Yuk Kien ; Liu, Jinyue ; Ang, Samantha Ya Lyn ; Loh, Ron Weng Yee ; Shao, Huilin ; Ching, Jianhong ; Wang, Yulan ; Yip, Stephen ; Tan, Patrick ; Li, Shang ; Low, David Chyi Yeu ; Phelan, Anne ; Rosser, Gabriel ; Tan, Nguan Soon ; Tang, Carol ; Ang, Beng Ti</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c180t-d79961e47a7584df74919b4cd858d8211eb33050f9cc10eb964e9317dedc25163</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Koh, Lynnette Wei Hsien</creatorcontrib><creatorcontrib>Pang, Qing You</creatorcontrib><creatorcontrib>Novera, Wisna</creatorcontrib><creatorcontrib>Lim, See Wee</creatorcontrib><creatorcontrib>Chong, Yuk Kien</creatorcontrib><creatorcontrib>Liu, Jinyue</creatorcontrib><creatorcontrib>Ang, Samantha Ya Lyn</creatorcontrib><creatorcontrib>Loh, Ron Weng Yee</creatorcontrib><creatorcontrib>Shao, Huilin</creatorcontrib><creatorcontrib>Ching, Jianhong</creatorcontrib><creatorcontrib>Wang, Yulan</creatorcontrib><creatorcontrib>Yip, Stephen</creatorcontrib><creatorcontrib>Tan, Patrick</creatorcontrib><creatorcontrib>Li, Shang</creatorcontrib><creatorcontrib>Low, David Chyi Yeu</creatorcontrib><creatorcontrib>Phelan, Anne</creatorcontrib><creatorcontrib>Rosser, Gabriel</creatorcontrib><creatorcontrib>Tan, Nguan Soon</creatorcontrib><creatorcontrib>Tang, Carol</creatorcontrib><creatorcontrib>Ang, Beng Ti</creatorcontrib><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Neuro-oncology (Charlottesville, Va.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Koh, Lynnette Wei Hsien</au><au>Pang, Qing You</au><au>Novera, Wisna</au><au>Lim, See Wee</au><au>Chong, Yuk Kien</au><au>Liu, Jinyue</au><au>Ang, Samantha Ya Lyn</au><au>Loh, Ron Weng Yee</au><au>Shao, Huilin</au><au>Ching, Jianhong</au><au>Wang, Yulan</au><au>Yip, Stephen</au><au>Tan, Patrick</au><au>Li, Shang</au><au>Low, David Chyi Yeu</au><au>Phelan, Anne</au><au>Rosser, Gabriel</au><au>Tan, Nguan Soon</au><au>Tang, Carol</au><au>Ang, Beng Ti</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>EZH2 functional dichotomy in reactive oxygen species-stratified glioblastoma</atitle><jtitle>Neuro-oncology (Charlottesville, Va.)</jtitle><addtitle>Neuro Oncol</addtitle><date>2024-10-07</date><risdate>2024</risdate><issn>1522-8517</issn><issn>1523-5866</issn><eissn>1523-5866</eissn><abstract>EZH2, well-known for its canonical methyltransferase activity in transcriptional repression in many cancers including glioblastoma (GBM), has an understudied non-canonical function critical for sustained tumor growth. Recent GBM consortial efforts reveal complex molecular heterogeneity for which therapeutic vulnerabilities correlated with subtype stratification remain relatively unexplored. Current enzymatic EZH2 inhibitors (EZH2inh) targeting its canonical SET domain show limited efficacy and lack durable response, suggesting that underlying differences in the non-canonical pathway may yield new knowledge. Here, we unveiled dual roles of the EZH2 CXC domain in therapeutically-distinct, reactive oxygen species (ROS)-stratified tumors.
We analyzed differentially expressed genes between ROS classes by examining cis-regulatory elements as well as clustering of activities and pathways to identify EZH2 as the key mediator in ROS-stratified cohorts. Pull-down assays and CRISPR knockout of EZH2 domains were used to dissect the distinct functions of EZH2 in ROS-stratified GBM cells. The efficacy of NF-κB-inducing kinase inhibitor (NIKinh) and standard-of-care temozolomide was evaluated using orthotopic patient-derived GBM xenografts.
In ROS(+) tumors, CXC-mediated co-interaction with RelB drives constitutive activation of non-canonical NF-κB2 signaling, sustaining the ROS(+) chemoresistant phenotype. In contrast, in ROS(-) subtypes, PRC2 methyltransferase activity represses canonical NF-κB. Addressing the lack of EZH2inh targeting its non-methyltransferase roles, we utilized a brain-penetrant NIKinh that disrupts EZH2-RelB binding, consequently prolonging survival in orthotopic ROS(+)-implanted mice.
Our findings highlight the functional dichotomy of the EZH2 CXC domain in governing ROS-stratified therapeutic resistance, thereby advocating for the development of therapeutic approaches targeting its non-canonical activities and underscoring the significance of patient stratification methodologies.</abstract><cop>England</cop><pmid>39373211</pmid><doi>10.1093/neuonc/noae206</doi><orcidid>https://orcid.org/0000-0002-1835-5083</orcidid><orcidid>https://orcid.org/0000-0002-8514-9861</orcidid><orcidid>https://orcid.org/0000-0003-0136-7341</orcidid></addata></record> |
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source | Oxford University Press Journals All Titles (1996-Current) |
title | EZH2 functional dichotomy in reactive oxygen species-stratified glioblastoma |
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