2. Academic Validation
  3. Iron-(Fe3+) dependent reactivation of telomerase drives colorectal cancers

Iron-(Fe3+) dependent reactivation of telomerase drives colorectal cancers

  • Cancer Discov. 2024 Jun 14. doi: 10.1158/2159-8290.CD-23-1379.
Raghuvaran Shanmugam 1,  Prativa Majee 1,  Wei Shi 1,  Mert Burak Ozturk 2,  Thamil Selvan Vaiyapuri 1,  Khaireen Idzham 1,  Anandhkumar Raju 1,  Seung Hee Shin 1,  Kerem Fidan 2,  Joo-Leng Low 3,  Joelle Yi Heng Chua 4,  Yap Choon Kong 5,  Ong Yue Qi 2,  Emile Tan 6,  Aik Yong Chok 6,  Isaac Seow-En 6,  Ian Wee 7,  Dominique Camat Macalinao 8,  Dawn Qingqing Chong 9,  Hong Yun Chang 10,  Fiona Lee 3,  Wei Qiang Leow 6,  Maki Murata-Hori 5,  Zhang Xiaoqian 5,  Chia Shumei 5,  Chris Soon Heng Tan 11,  Ramanuj Dasgupta 3,  Iain Beehuat Tan 9,  Vinay Tergaonkar 12
Affiliations

Affiliations

  • 1 Institute of Molecular and Cell Biology, Singapore, Singapore.
  • 2 Institute of Molecular and Cell Biology, Singapore.
  • 3 Genome Institute of Singapore, Singapore, Singapore.
  • 4 Laboratory of NFκB Signalling, Institute of Molecular and Cell Biology (IMCB), A*STAR (Agency for Science, Technology and Research), Singapore 138673, Singapore, Singapore, Singapore.
  • 5 Genome Institute of Singapore, Singapore.
  • 6 Singapore General Hospital, Singapore, Singapore.
  • 7 Singapore General Hospital, Singapore.
  • 8 National Cancer Centre Singapore, Singapore.
  • 9 National Cancer Centre Singapore, Singapore, Singapore.
  • 10 Experimental Drug Development Centre, Singapore.
  • 11 Southern University of Science and Technology, China.
  • 12 Laboratory of NF- kappaB signalling, Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673., Singapore, Singapore.
PMID: 38885349 DOI: 10.1158/2159-8290.CD-23-1379
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.

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