1. Academic Validation
  2. 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


  • 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.

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.