Iron-(Fe3+)-Dependent Reactivation of Telomerase Drives Colorectal Cancers
Raghuvaran Shanmugam, Prativa Majee, Wei Shi, Mert B. Ozturk, Thamil S. Vaiyapuri, Khaireen Idzham, Anandhkumar Raju, Seung Hee Shin, Kerem Fidan, Joo-Leng Low, Joelle Y.H. Chua, Yap C. Kong, Ong Y. Qi, Emile Tan, Aik Yong Chok, Isaac Seow‐En, Ian Wee, Dominique C. Macalinao, Dawn Q. Chong, Hong Y. Chang, Fiona Lee, Wei Qiang Leow, Maki Murata‐Hori, Zhang Xiaoqian, Chia Shumei, Chris Soon Heng Tan, Ramanuj DasGupta, Iain Beehuat Tan, Vinay Tergaonkar
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.