Raghuvaran Shanmugam, Prativa Majee, Wei Shi, Mert Burak Ozturk, Thamil Selvan Vaiyapuri, Khaireen Idzham, Anandhkumar Raju, Seung Hee Shin, Kerem Fidan, Joo-Leng Low, Joelle Yi Heng Chua, Yap Choon Kong, Ong Yue Qi, Emile Tan, Aik Yong Chok, Isaac Seow-En, Ian Wee, Dominique Camat Macalinao, Dawn Qingqing Chong, Hong Yun Chang, Fiona Lee, Wei Qiang Leow, Maki Murata-Hori, Zhang Xiaoqian, Chia Shumei, Chris Soon Heng Tan, Ramanuj Dasgupta, Iain Beehuat Tan, Vinay Tergaonkar
{"title":"Iron-(Fe3+) dependent reactivation of telomerase drives colorectal cancers.","authors":"Raghuvaran Shanmugam, Prativa Majee, Wei Shi, Mert Burak Ozturk, Thamil Selvan Vaiyapuri, Khaireen Idzham, Anandhkumar Raju, Seung Hee Shin, Kerem Fidan, Joo-Leng Low, Joelle Yi Heng Chua, Yap Choon Kong, Ong Yue Qi, Emile Tan, Aik Yong Chok, Isaac Seow-En, Ian Wee, Dominique Camat Macalinao, Dawn Qingqing Chong, Hong Yun Chang, Fiona Lee, Wei Qiang Leow, Maki Murata-Hori, Zhang Xiaoqian, Chia Shumei, Chris Soon Heng Tan, Ramanuj Dasgupta, Iain Beehuat Tan, Vinay Tergaonkar","doi":"10.1158/2159-8290.CD-23-1379","DOIUrl":null,"url":null,"abstract":"<p><p>Over-consumption of iron-rich red meat and hereditary or genetic iron overload are associated with increased risk of colorectal carcinogenesis, yet the mechanistic basis of how metal-mediated signaling leads to oncogenesis remains enigmatic. Using fresh colorectal cancer (CRC) samples we identify Pirin, an iron sensor, that overcomes a rate-limiting step in oncogenesis, by re-activating the dormant human-reverse-transcriptase (hTERT) subunit of telomerase holoenzyme in an iron-(Fe3+)-dependent-manner and thereby drives CRCs. Chemical genetic screens combined with isothermal-dose response fingerprinting and mass-spectrometry identified a small molecule SP2509, that specifically inhibits Pirin-mediated hTERT reactivation in CRCs by competing with iron-(Fe3+) binding. Our findings, first to document how metal ions reactivate telomerase, provide a molecular mechanism for the well-known association between red meat, and increased incidence of CRCs. Small molecules like SP2509 represent a novel modality to target telomerase that acts as driver of 90% human cancers and is yet to be targeted in clinic.</p>","PeriodicalId":9430,"journal":{"name":"Cancer discovery","volume":null,"pages":null},"PeriodicalIF":29.7000,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cancer discovery","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1158/2159-8290.CD-23-1379","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ONCOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Over-consumption of iron-rich red meat and hereditary or genetic iron overload are associated with increased risk of colorectal carcinogenesis, yet the mechanistic basis of how metal-mediated signaling leads to oncogenesis remains enigmatic. Using fresh colorectal cancer (CRC) samples we identify Pirin, an iron sensor, that overcomes a rate-limiting step in oncogenesis, by re-activating the dormant human-reverse-transcriptase (hTERT) subunit of telomerase holoenzyme in an iron-(Fe3+)-dependent-manner and thereby drives CRCs. Chemical genetic screens combined with isothermal-dose response fingerprinting and mass-spectrometry identified a small molecule SP2509, that specifically inhibits Pirin-mediated hTERT reactivation in CRCs by competing with iron-(Fe3+) binding. Our findings, first to document how metal ions reactivate telomerase, provide a molecular mechanism for the well-known association between red meat, and increased incidence of CRCs. Small molecules like SP2509 represent a novel modality to target telomerase that acts as driver of 90% human cancers and is yet to be targeted in clinic.
期刊介绍:
Cancer Discovery publishes high-impact, peer-reviewed articles detailing significant advances in both research and clinical trials. Serving as a premier cancer information resource, the journal also features Review Articles, Perspectives, Commentaries, News stories, and Research Watch summaries to keep readers abreast of the latest findings in the field. Covering a wide range of topics, from laboratory research to clinical trials and epidemiologic studies, Cancer Discovery spans the entire spectrum of cancer research and medicine.