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
  • 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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