Iron-(Fe3+)-Dependent Reactivation of Telomerase Drives Colorectal Cancers.

IF 29.7 1区 医学 Q1 ONCOLOGY
Raghuvaran Shanmugam, Prativa Majee, Wei Shi, Mert B Ozturk, Thamil S Vaiyapuri, Khaireen Idzham, Anandhkumar Raju, Seung H Shin, Kerem Fidan, Joo-Leng Low, Joelle Y H Chua, Yap C Kong, Ong Y Qi, Emile Tan, Aik Y Chok, Isaac Seow-En, Ian Wee, Dominique C Macalinao, Dawn Q Chong, Hong Y Chang, Fiona Lee, Wei Q Leow, Maki Murata-Hori, Zhang Xiaoqian, Chia Shumei, Chris S H Tan, Ramanuj Dasgupta, Iain B Tan, Vinay Tergaonkar
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引用次数: 0

Abstract

Over-consumption of iron-rich red meat and hereditary or genetic iron overload are associated with an increased risk of colorectal carcinogenesis, yet the mechanistic basis of how metal-mediated signaling leads to oncogenesis remains enigmatic. Using fresh colorectal cancer samples we identify Pirin, an iron sensor, that overcomes a rate-limiting step in oncogenesis, by reactivating the dormant human telomerase reverse transcriptase (hTERT) subunit of the telomerase holoenzyme in an iron-(Fe3+)-dependent manner and thereby drives colorectal cancers. 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 colorectal cancers 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 colorectal cancers. Small molecules like SP2509 represent a novel modality to target telomerase that acts as a driver of 90% of human cancers and is yet to be targeted in clinic. Significance: We show how iron-(Fe3+) in collusion with genetic factors reactivates telomerase, providing a molecular mechanism for the association between iron overload and increased incidence of colorectal cancers. Although no enzymatic inhibitors of telomerase have entered the clinic, we identify SP2509, a small molecule that targets telomerase reactivation and function in colorectal cancers.

铁(Fe3+)依赖性端粒酶再激活驱动结直肠癌。
过量食用富含铁的红肉以及遗传性或基因性铁超载与结直肠癌发生风险的增加有关,但金属介导的信号转导如何导致肿瘤发生的机理基础仍然是个谜。通过使用新鲜的结直肠癌(CRC)样本,我们发现了铁传感器 Pirin,它能以铁(Fe3+)依赖的方式重新激活端粒酶全酶中休眠的人类逆转录酶(hTERT)亚基,从而克服致癌过程中的限速步骤,并驱动 CRCs。化学遗传筛选与等温剂量反应指纹图谱和质谱分析相结合,发现了一种小分子 SP2509,它能通过与铁(Fe3+)结合竞争,特异性地抑制 Pirin 介导的 CRC 中 hTERT 的再激活。我们的发现首次记录了金属离子如何重新激活端粒酶,为众所周知的红肉与 CRC 发病率增加之间的联系提供了分子机制。像SP2509这样的小分子药物代表了一种靶向端粒酶的新方法,端粒酶是90%人类癌症的驱动因素,但在临床上尚未成为靶向药物。
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来源期刊
Cancer discovery
Cancer discovery ONCOLOGY-
CiteScore
22.90
自引率
1.40%
发文量
838
审稿时长
6-12 weeks
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.
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